Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.

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Impact of microbiota on central nervous system and neurological diseases: the gut-brain axis.

Ubiquitination has emerged as a crucial mechanism that regulates signal transduction in diverse biological processes, including different aspects of immune functions. Ubiquitination regulates pattern-recognition receptor signaling that mediates both innate immune responses and dendritic cell maturation required for initiation of adaptive immune responses. Ubiquitination also regulates the development, activation, and differentiation of T cells, thereby maintaining efficient adaptive immune responses to pathogens and immunological tolerance to self-tissues. Like phosphorylation, ubiquitination is a reversible reaction tightly controlled by the opposing actions of ubiquitin ligases and deubiquitinases. Deregulated ubiquitination events are associated with immunological disorders, including autoimmune and inflammatory diseases.

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Ubiquitin signaling in immune responses

TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses.

TRIM11 Suppresses AIM2 Inflammasome by Degrading AIM2 via p62-Dependent Selective Autophagy

Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets.

NLRC5 is an important regulator in innate immune responses. However, the ability of NLRC5 to inhibit NF-κB activation is controversial in different cell types. How dynamic modification of NLRC5 shapes NF-κB signaling remains unknown. We demonstrated that NLRC5 undergoes robust ubiquitination by TRAF2/6 after lipopolysaccharide treatment, which leads to dissociation of the NLRC5–IκB kinase complex. Experimental and mathematical analyses revealed that the K63-linked ubiquitination of NLRC5 at lysine 1,178 generates a coherent feedforward loop to further sensitize NF-κB activation. Meanwhile, we found USP14 specifically removes the polyubiquitin chains from NLRC5 to enhance NLRC5-mediated inhibition of NF-κB signaling. Furthermore, we found that different cell types may exhibit different sensitivities to NF-κB activation in response to NLRC5 ablation, possibly as a result of the various intrinsic levels of deubiquitinases and NLRC5. This might partially reconcile controversial studies and explain why NLRC5 exhibits diverse inhibitory efficiencies. Collectively, our results provide the regulatory mechanisms of reversible NLRC5 ubiquitination and its role in the dynamic control of innate immunity.

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Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch

Abstract Ubiquitination is a highly conserved and fundamental posttranslational modification (PTM) in all eukaryotes regulating thousands of proteins. The RING (really interesting new gene) finger (RNF) protein, containing the RING domain, exerts E3 ubiquitin ligase that mediates the covalent attachment of ubiquitin (Ub) to target proteins. Multiple reviews have summarized the critical roles of the tripartite-motif (TRIM) protein family, a subgroup of RNF proteins, in various diseases, including cancer, inflammatory, infectious, and neuropsychiatric disorders. Except for TRIMs, since numerous studies over the past decades have delineated that other RNF proteins also exert widespread involvement in several diseases, their importance should not be underestimated. This review summarizes the potential contribution of dysregulated RNF proteins, except for TRIMs, to the pathogenesis of some diseases, including cancer, autoimmune diseases, and neurodegenerative disorder. Since viral infection is broadly involved in the induction and development of those diseases, this manuscript also highlights the regulatory roles of RNF proteins, excluding TRIMs, in the antiviral immune responses. In addition, we further discuss the potential intervention strategies targeting other RNF proteins for the prevention and therapeutics of those human diseases. 

/pdf/the-ring-finger-protein-family-in-health-and-disease-5kdriri5.pdf

The RING finger protein family in health and disease

The pandemic coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is currently the most formidable challenge to humankind. Understanding the complicated virus‐host interplay is crucial for fighting against viral infection. A growing number of studies point to the critical roles of RING (really interesting new gene) finger (RNF) proteins during SARS‐CoV‐2 infection. RNF proteins exert direct antiviral activity by targeting genome and envelope glycoproteins of SARS‐CoV‐2. Additionally, some RNF members serve as potent regulators for antiviral innate immunity and antibody‐dependent neutralization of SARS‐CoV‐2. Notably, SARS‐CoV‐2 also hijacks the RNF proteins‐mediated ubiquitination process to evade host antiviral innate immunity and enhance viral replication. In this mini‐review, we discuss the diverse antiviral mechanisms of RNF proteins and viral immune evasion in an RNF proteins‐dependent manner. Understanding the crosstalk between RNF proteins and SARS‐CoV‐2 infection would help design potential novel targets for COVID‐19 treatment.

When RING finger family proteins meet SARS‐CoV‐2

The interferons (IFNs) responses to viral infection are heterogeneous, while the underlying mechanisms for variability among cells are still not clear. In this study, we developed a hybrid model to systematically identify the sources of IFN induction heterogeneity. The experiment-integrated simulation demonstrated that the viral dose/type, the diversity in transcriptional factors activation and the intercellular paracrine signaling could strikingly shape the heterogeneity of IFN expression. We further determined that the IFNβ and IFNλ1 induced diverse dynamics of IFN-stimulated genes (ISGs) production. Collectively, our findings revealed the intracellular and intercellular mechanisms contributing to cell-to-cell variation in IFN induction, and further demonstrated the significant effects of IFN heterogeneity on antagonizing viruses.

Chunmei Cai

Papers

Reversible ubiquitination shapes NLRC5 function and modulates NF-κB activation switch

The RING finger protein family in health and disease

When RING finger family proteins meet SARS‐CoV‐2

Integrated modeling and analysis of intracellular and intercellular mechanisms in shaping the interferon response to viral infection.

Comparative genomic analysis of high-altitude adaptation for Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus.