Showing papers on "Secretion published in 2023"

Identification of protein secretion systems in bacterial genomes using MacSyFinder version 2

Abstract: Protein secretion systems are complex molecular machineries that translocate proteins through the outer membrane and sometimes through multiple other barriers. They have evolved by co-option of components from other envelope-associated cellular machineries, making them sometimes difficult to identify and discriminate. Here, we describe how to identify protein secretion systems in bacterial genomes using the MacSyFinder program. This flexible computational tool uses the knowledge gathered from experimental studies to identify homologous systems in genome data. It can be used with a set of pre-defined MacSyFinder models—”TXSScan”, to identify all major secretion systems of diderm bacteria (i.e., with inner and LPS-containing outer membranes) as well as evolutionarily related cell appendages (pili and flagella). For this, it identifies and clusters co-localized genes encoding proteins of secretion systems using sequence similarity search with Hidden Markov Model (HMM) protein profiles. Finally, it checks if the clusters’ genetic content and genomic organization satisfy the constraints of the model. TXSScan models can be altered in the command line or customized to search for variants of known secretion systems. Models can also be built from scratch to identify novel systems. In this chapter, we describe a complete pipeline of analysis, starting from i) the integration of information from a reference set of experimentally studied systems, ii) the identification of conserved proteins and the construction of their HMM protein profiles, iii) the definition and optimization of “macsy-models”, and iv) their use and online distribution as tools to search genomic data for secretion systems of interest. MacSyFinder is available here: https://github.com/gem-pasteur/macsyfinder, and MacSyFinder models here: https://github.com/macsy-models.

A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells

Abstract: Cancers represent complex autonomous systems, displaying self‐sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell's ability to “secrete‐and‐sense” growth factors (GFs): a poorly understood phenomenon. Using an integrated computational and experimental approach, here we dissect the impact of a feedback‐coupled GTPase circuit within the secretory pathway that imparts secretion‐coupled autonomy. The circuit is assembled when the Ras‐superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giαβγ and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed‐loop control, allow the two GTPases to coregulate each other, and convert the expected switch‐like behavior of Arf1‐dependent secretion into an unexpected dose–response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self‐sustained by stimulus‐proportionate secretion. Proteomic studies and protein–protein interaction network analyses pinpoint GFs (e.g., the epidermal GF) as key stimuli for such self‐sustenance. Findings highlight how the enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion‐coupled autonomy of growth factors.

Intestinal mucus components and secretion mechanisms: what we do and do not know

Abstract: Abstract Damage to the colon mucus barrier, the first line of defense against microorganisms, is an important determinant of intestinal diseases such as inflammatory bowel disease and colorectal cancer, and disorder in extraintestinal organs. The mucus layer has attracted the attention of the scientific community in recent years, and with the discovery of new mucosal components, it has become increasingly clear that the mucosal barrier is a complex system composed of many components. Moreover, certain components are jointly involved in regulating the structure and function of the mucus barrier. Therefore, a comprehensive and systematic understanding of the functional components of the mucus layer is clearly warranted. In this review, we summarize the various functional components of the mucus layer identified thus far and describe their unique roles in shaping mucosal structure and function. Furthermore, we detail the mechanisms underlying mucus secretion, including baseline and stimulated secretion. In our opinion, baseline secretion can be categorized into spontaneous Ca 2+ oscillation-mediated slow and continuous secretion and stimulated secretion, which is mediated by massive Ca 2+ influx induced by exogenous stimuli. This review extends the current understanding of the intestinal mucus barrier, with an emphasis on host defense strategies based on fortification of the mucus layer.

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

Abstract: Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin‐family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non‐classical secretion of IL‐1 family cytokines that amplify host‐beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL‐1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase‐1 to generate GSDMD macropores that mediate IL‐1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL‐1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase‐1‐mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD‐dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD‐dependent mechanisms for export of bioactive IL‐1β. Rather, neutrophils employ cell‐specific mechanisms to conditionally engage GSDMD‐mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass

Abstract: Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and β-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced β-cell function and decreased β-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in β-cells by inhibiting Ca2+ re-uptake via SERCA2 and inducing Ca2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving β-cell mass. Moreover, treatment with alnustone inhibits THADA's function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies.

Cross-talk between cancer and Pseudomonas aeruginosa mediates tumor suppression

Abstract: Microorganisms living at many sites in the human body compose a complex and dynamic community. Accumulating evidence suggests a significant role for microorganisms in cancer, and therapies that incorporate bacteria have been tried in various types of cancer. We previously demonstrated that cupredoxin azurin secreted by the opportunistic pathogen Pseudomonas aeruginosa, enters human cancer cells and induces apoptotic death1-4. However, the physiological interactions between P. aeruginosa and humans and their role in tumor homeostasis are largely unknown. Here, we show that P. aeruginosa upregulated azurin secretion in response to increasing numbers of and proximity to cancer cells. Conversely, cancer cells upregulated aldolase A secretion in response to increasing proximity to P. aeruginosa, which also correlated with enhanced P. aeruginosa adherence to cancer cells. Additionally, we show that cancer patients had detectable P. aeruginosa and azurin in their tumors and exhibited increased overall survival when they did, and that azurin administration reduced tumor growth in transgenic mice. Our results suggest host-bacterial symbiotic mutualism acting as a diverse adjunct to the host defense system via inter-kingdom communication mediated by the evolutionarily conserved proteins azurin and human aldolase A. This improved understanding of the symbiotic relationship of bacteria with humans indicates the potential contribution to tumor homeostasis.

Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome

Abstract: Inflammation driven by the NLRP3 inflammasome is coordinated through multiple signaling pathways and is regulated by subcellular organelles. Here, we tested the hypothesis that NLRP3 senses disrupted endosome trafficking to trigger inflammasome formation and inflammatory cytokine secretion. NLRP3-activating stimuli disrupted endosome trafficking and triggered localization of NLRP3 to vesicles positive for endolysosomal markers and for the inositol lipid PI4P. Chemical disruption of endosome trafficking sensitized macrophages to the NLRP3 activator imiquimod, driving enhanced inflammasome activation and cytokine secretion. Together, these data suggest that NLRP3 can sense disruptions in the trafficking of endosomal cargoes, which may explain in part the spatial activation of the NLRP3 inflammasome. These data highlight mechanisms that could be exploited in the therapeutic targeting of NLRP3. Description The NLRP3 inflammasome senses and is activated by perturbations in endosomal trafficking. Inflammation-inducing traffic jams The NLRP3 inflammasome assembles and is activated by diverse cellular stresses to produce proinflammatory cytokines. Lee et al. investigated whether the NLRP3 inflammasome was activated by disruptions in endosomal trafficking. By analyzing various cell types, including bone marrow-derived macrophages, the authors found that NLRP3-activating stimuli resulted in perturbations in endosomal trafficking and conversely, that chemical interference with endosomal trafficking potentiated NLRP3 activation, although it was insufficient to activate NLRP3 by itself. Activated NLRP3 was recruited to endolysosomal vesicles, where it colocalized with the lipid PI4P, which the authors speculated may be the additional stimulus required for NLRP3 activation. Thus, NLRP3 senses and is activated by cellular stress resulting from disordered endosomal trafficking. —WW

Knock-sideways by inducible ER retrieval enables a novel approach for studying Plasmodium secreted proteins

Abstract: Malaria parasites uniquely depend on protein secretion for their obligate intracellular lifestyle but approaches for dissecting Plasmodium secreted protein functions are limited. We report knockER, a novel DiCre-mediated knock-sideways approach to sequester secreted proteins in the ER by inducible fusion with a KDEL ER-retrieval sequence. We show conditional ER sequestration of diverse proteins is not generally toxic, enabling loss-of-function studies. We employed knockER in multiple Plasmodium species to interrogate the trafficking, topology and function of an assortment of proteins that traverse the secretory pathway to diverse compartments including the apicoplast (ClpB1), rhoptries (RON6), dense granules and parasitophorous vacuole (EXP2, PTEX150, HSP101). Taking advantage of the unique ability to redistribute secreted proteins from their terminal destination to the ER, we reveal vacuolar levels of the PTEX translocon component HSP101 but not PTEX150 are maintained in excess of what is required to sustain effector protein export into the erythrocyte. Intriguingly, vacuole depletion of HSP101 hypersensitized parasites to a destabilization tag that inhibits HSP101-PTEX complex formation but not to translational knockdown of the entire HSP101 pool, illustrating how redistribution of a target protein by knockER can be used to query function in a compartment-specific manner. Collectively, our results establish knockER as a novel tool for dissecting secreted protein function with sub-compartmental resolution that should be widely amenable to genetically tractable eukaryotes. Significance Protein trafficking and secretion through the endomembrane system is a defining feature of eukaryotes. The secretory pathway is central to the unique biology and pathology of the obligate intracellular malaria parasite, however tools for studying secreted protein function are limited. Knock-sideways is a powerful mutagenesis strategy that conditionally sequesters a protein away from its site of function but is generally not applicable to secreted proteins. We developed a simple approach to conditionally sequester Plasmodium secreted proteins in the ER by inducible C-terminal fusion with a KDEL ER-retrieval sequence that can be used for trafficking, topology and loss-of-function studies. The knockER strategy is broadly applicable to functional dissection of proteins that traverse the eukaryotic secretory pathway.

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection

Abstract: Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection.

An Anaplasma phagocytophilum T4SS effector, AteA, is essential for tick infection

Abstract: Pathogens must adapt to disparate environments in permissive host species, a feat that is especially pronounced for vector-borne microbes, which transition between vertebrate hosts and arthropod vectors to complete their lifecycles. Most knowledge about arthropod-vectored bacterial pathogens centers on their life in the mammalian host, where disease occurs. However, disease outbreaks are driven by the arthropod vectors. Adapting to the arthropod is critical for obligate intracellular rickettsial pathogens, as they depend on eukaryotic cells for survival. To manipulate the intracellular environment, these bacteria use Type IV Secretion Systems (T4SS) to deliver effectors into the host cell. To date, few rickettsial T4SS translocated effectors have been identified and have only been examined in the context of mammalian infection. We identified an effector from the tick-borne rickettsial pathogen Anaplasma phagocytophilum, HGE1_02492, as critical for survival in tick cells and acquisition by ticks in vivo. Conversely, HGE1_02492 was dispensable during mammalian cell culture and murine infection. We show HGE1_02492 is translocatable in a T4SS-dependent manner to the host cell cytosol. In eukaryotic cells, the HGE1_02492 localized with cortical actin filaments, which is dependent on multiple sub-domains of the protein. HGE1_02492 is the first arthropod-vector specific T4SS translocated effector identified from a rickettsial pathogen. Moreover, the subcellular target of HGE1_02492 suggests that A. phagocytophilum is manipulating actin to enable arthropod colonization. Based on these findings, we propose the name AteA for Anaplasma (phagocytophilum) tick effector A. Altogether, we show that A. phagocytophilum uses distinct strategies to cycle between mammals and arthropods. Importance Ticks are the number one vector of pathogens for livestock worldwide and for humans in the US. The biology of tick transmission is an understudied area. Understanding this critical interaction could provide opportunities to affect the course of disease spread. In this study we examined the zoonotic tick-borne agent Anaplasma phagocytophilum and identified a secreted protein, AteA, that is expressed in a tick-specific manner. These secreted proteins, termed effectors, are the first proteins to interact with the host environment. AteA is essential for survival in ticks and appears to interact with cortical actin. Most effector proteins are studied in the context of the mammalian host; however, understanding how this unique set of proteins affect tick transmission is critical to developing interventions.

Heterogeneity of the group B streptococcal type VII secretion system and influence on colonization of the female genital tract

Abstract: Type VIIb secretion systems (T7SSb) in Gram-positive bacteria facilitate physiology, interbacterial competition, and/or virulence via EssC ATPase-driven secretion of small ɑ-helical proteins and toxins. Recently, we characterized T7SSb in group B Streptococcus (GBS), a leading cause of infection in newborns and immunocompromised adults. GBS T7SS comprises four subtypes based on variation in the C-terminus of EssC and the repertoire of downstream effectors; however, the intra-species diversity of GBS T7SS and impact on GBS-host interactions remains unknown. Bioinformatic analysis indicates that GBS T7SS loci encode subtype-specific putative effectors, which have low inter-species and inter-subtype homology but contain similar domains/motifs and therefore may serve similar functions. We further identify orphaned GBS WXG100 proteins. Functionally, we show that GBS T7SS subtype I and III strains secrete EsxA in vitro and that in subtype I strain CJB111, esxA1 appears to be differentially transcribed from the T7SS operon. Further, we observe subtype-specific effects of GBS T7SS on host colonization, as subtype I but not subtype III T7SS promotes GBS vaginal persistence. Finally, we observe that T7SS subtypes I and II are the predominant subtypes in clinical GBS isolates. This study highlights the potential impact of T7SS heterogeneity on host-GBS interactions.

Biochar assists phosphate solubilizing bacteria to resist combined Pb and Cd stress by promoting acid secretion and extracellular electron transfer.

Abstract: Microorganisms have difficulty surviving and performing remediation functions in mixed systems with high concentrations of Pb and Cd. Biochar has the potential to assist microorganism remediation as an excellent adsorbent for heavy metals. In this study, pig manure biochar (PMB) was used to assist phosphorus solubilizing bacteria (PSB) to explore the mineralization protection and biofeedback mechanism of biochar on PSB under mixed stress of 1000 mg/L Pb2+ and 500 mg/L Cd2+. The adsorption results showed that the removal of Pb2+ and Cd2+ by PMB+PSB was 148.77% and 72.27% higher than that by PSB. Meanwhile, the non-bioavailable fraction of Cd2+ and acid-soluble fraction of Pb2+ in PMB+PSB were increased by 9% and 3%, respectively. Mineralogical and microbial secretion results confirm that showed that the acidic soluble fraction and non-bioavailable fraction were mostly Pb/Cd-carbonate and Pb/Cd-phosphate. The pore adsorption and precipitation (carbonate) of biochar were able to reduce the exposure of PSB to Pb/Cd and the background stress concentration, thus stimulating the biological positive feedback effect of PSB and forming a microenvironment in the cell periphery. The vesicle detoxification and extracellular polymeric substance protection mechanism of PSB were improved under biochar protection, and the individual size and activity of PSB cells were enhanced. Besides, citric acid release from PSB (28.85% increase) accelerated the dissolution of unstable Cd-carbonate, thereby releasing a large amount of Cd2+ to compete with Pb2+ for PO43-. Thus, the protection of biochar and the positive feedback effect of PSB could reduce the biotoxicity of Cd2+ in the stress system by preferentially forming a stable Cd-phosphate. In addition, the excellent electrical conductivity and organic material adsorption of biochar increased the extracellular electron transport rate of microorganisms, which further accelerated the mineralization and immobilization of Pb2+ and Cd2+, so as to ensure the repair effect of PSB on heavy metals.

Plant commensal type VII secretion system causes iron leakage from roots to promote colonization.

Abstract: Competition for iron is an important factor for microbial niche establishment in the rhizosphere. Pathogenic and beneficial symbiotic bacteria use various secretion systems to interact with their hosts and acquire limited resources from the environment. Bacillus spp. are important plant commensals that encode a type VII secretion system (T7SS). However, the function of this secretion system in rhizobacteria-plant interactions is unclear. Here we use the beneficial rhizobacterium Bacillus velezensis SQR9 to show that the T7SS and the major secreted protein YukE are critical for root colonization. In planta experiments and liposome-based experiments demonstrate that secreted YukE inserts into the plant plasma membrane and causes root iron leakage in the early stage of inoculation. The increased availability of iron promotes root colonization by SQR9. Overall, our work reveals a previously undescribed role of the T7SS in a beneficial rhizobacterium to promote colonization and thus plant-microbe interactions.

Integrative structural analysis of the type III secretion system needle complex from Shigella flexneri

Abstract: The type III secretion system (T3SS) is a large, transmembrane protein machinery used by various pathogenic gram‐negative bacteria to transport virulence factors into the host cell during infection. Understanding the structure of T3SSs is crucial for future developments of therapeutics that could target this system. However, much of the knowledge about the structure of T3SS is available only for Salmonella, and it is unclear how this large assembly is conserved across species. Here, we combined cryo‐electron microscopy, cross‐linking mass spectrometry, and integrative modeling to determine the structure of the T3SS needle complex from Shigella flexneri. We show that the Shigella T3SS exhibits unique features distinguishing it from other structurally characterized T3SSs. The secretin pore complex adopts a new fold of its C‐terminal S domain and the pilotin MxiM[SctG] locates around the outer surface of the pore. The export apparatus structure exhibits a conserved pseudohelical arrangement but includes the N‐terminal domain of the SpaS[SctU] subunit, which was not present in any of the previously published virulence‐related T3SS structures. Similar to other T3SSs, however, the apparatus is anchored within the needle complex by a network of flexible linkers that either adjust conformation to connect to equivalent patches on the secretin oligomer or bind distinct surface patches at the same height of the export apparatus. The conserved and unique features delineated by our analysis highlight the necessity to analyze T3SS in a species‐specific manner, in order to fully understand the underlying molecular mechanisms of these systems. The structure of the type III secretion system from Shigella flexneri delineates conserved and unique features, which could be used for the development of broad‐range therapeutics.

Termite exocrine systems: a review of current knowledge

Abstract: In this review, we summarize the 22 exocrine glands hitherto described for termites (Isoptera), highlighting their distribution, morphological features, and likely function. The secretion from such glands displays a very important role in termite communication, but is also attributed to many other activities performed by these insects, including defense, building, and foraging, as well as physiological processes such as the synthesis of digestive enzymes, and antiseptic and lubricant compounds. Here, glands are divided into those associated with termite mouthparts and other head appendages, tegumentary glands with epithelial arrangement, those related to the reproductive apparatus, and glands which do not fit into these divisions. The exocrine systems in termites may be composed of classes 1, 2, and 3 secretory cells, which differ in how the glandular secretion is released. Moreover, they may exhibit a varied composition of secretory cell classes. Different glands may be involved in specific tasks and therefore produce specific compounds, although there are cases in which the same content is secreted by different glands, suggesting a functional plasticity. The chemical nature of these secretions and their role are well known for some glands, such as the frontal, salivary, tergal, and sternal ones. On the other hand, such aspects remain speculative or completely unknown for other glands. The number of termite exocrine glands is extremely low when compared to those described for eusocial Hymenoptera, and is a likely consequence of the higher diversity of species and chemical communication in the latter group. Moreover, vibroacoustic signals represent an important type of communication in termites. Further studies are encouraged to provide new insights into the occurrence and function of the exocrine systems in termites and how they modulate the different activities displayed by them.

Extracellular RNA: mechanisms of secretion and potential functions

Abstract: Abstract Extracellular RNA (exRNA) has long been considered as cellular waste that plants can degrade and utilize to recycle nutrients. However, recent findings highlight the need to reconsider the biological significance of RNAs found outside of plant cells. A handful of studies suggest that the exRNA repertoire, which turns out to be an extremely heterogenous group of non-coding RNAs, comprises species as small as a dozen nucleotides to hundreds of nucleotides long. They are found mostly in free form or associated with RNA-binding proteins, while very few are found inside extracellular vesicles (EVs). Despite their low abundance, small RNAs associated with EVs have been a focus of exRNA research due to their putative role in mediating trans-kingdom RNAi. Therefore, non-vesicular exRNAs have remained completely under the radar until very recently. Here we summarize our current knowledge of the RNA species that constitute the extracellular RNAome and discuss mechanisms that could explain the diversity of exRNAs, focusing not only on the potential mechanisms involved in RNA secretion but also on post-release processing of exRNAs. We will also share our thoughts on the putative roles of vesicular and extravesicular exRNAs in plant–pathogen interactions, intercellular communication, and other physiological processes in plants.

Activated SOX9+ renal epithelial cells promote kidney repair through secreting factors

Abstract: A broad spectrum of lethal kidney diseases involves the irreversible destruction of the tubular structures, leading to renal function loss. Following injury, a spectrum of tissue‐resident epithelial stem/progenitor cells are known to be activated and then differentiate into mature renal cells to replace the damaged renal epithelium. Here, however, we reported an alternative way that tissue‐resident cells could be activated to secrete multiple factors to promote organ repair. At single‐cell resolution, we showed that the resident SOX9+ renal epithelial cells (RECs) could expand in the acutely injured kidney of both mouse and human. Compared to other cells, the SOX9+ RECs overexpressed much more secretion related genes, whose functions were linked to kidney repair pathways. We also obtained long‐term, feeder‐free cultured SOX9+ RECs from human urine and analysed their secretory profile at both transcriptional and proteomic levels. Engraftment of cultured human SOX9+ RECs or injection of its conditional medium facilitated the regeneration of renal tubular and glomerular epithelium, probably through stimulating endogenous REC self‐activation and mediating crosstalk with other renal cells. We also identified S100A9 as one of the key factors in the SOX9+ REC secretome. Altogether, the abilities to extensively propagate SOX9+ RECs in culture whilst concomitantly maintaining their intrinsic secretory capacity suggest their future application in cell‐free therapies and regeneration medicine.

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury

Abstract: Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.

Sec22b is a critical and nonredundant regulator of plasma cell maintenance

Abstract: Significance Despite their central role in health and disease, the cellular mechanisms underlying how plasma cells persist while producing large quantities of antibodies are still poorly understood. In this paper, we describe that plasma cell survival is under the strict dependency of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) molecule Sec22b. We showed that this molecule is a key regulator of endoplasmic reticulum and mitochondrial structure in plasma cells, and in its absence, the humoral immune response is abrogated. Our findings have important implications for our understanding of antibody-mediated immunity but also open avenues for targeting plasma cells in pathological contexts.