Guido Kroemer

Bio: Guido Kroemer is an academic researcher from Institut Gustave Roussy. The author has contributed to research in topics: Programmed cell death & Autophagy. The author has an hindex of 236, co-authored 1404 publications receiving 246571 citations. Previous affiliations of Guido Kroemer include Karolinska Institutet & Spanish National Research Council.

Syncytial apoptosis signaling network induced by the HIV-1 envelope glycoprotein complex: An overview

Abstract: Infection by human immunodeficiency virus-1 (HIV-1) is associated with a progressive decrease in CD4 T-cell numbers and the consequent collapse of host immune defenses. The major pathogenic mechanism of AIDS is the massive apoptotic destruction of the immunocompetent cells, including uninfected cells. The latter process, also known as by-stander killing, operates by various mechanisms one of which involves the formation of syncytia which undergo cell death by following a complex pathway. We present here a detailed and curated map of the syncytial apoptosis signaling network, aimed at simplifying the whole mechanism that we have characterized at the molecular level in the last 15 years. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner software and encompasses 36 components (proteins/genes) and 54 interactions. The simplification of this complex network paves the way for the development of novel therapeutic strategies to eradicate HIV-1 infection. Agents that induce the selective death of HIV-1-elicited syncytia might lead to the elimination of viral reservoirs and hence constitute an important complement to current antiretroviral therapies.

Peroxisome: the new player in ferroptosis

Abstract: A recent paper published in Nature by Zou et al. reported that peroxisomes, membrane-bound oxidative organelles, contribute to ferroptosis through the biosynthesis of plasmalogens for lipid peroxidation (Fig. 1). These observations provide new insights into the lipid metabolic basis of ferroptotic cell death. Cell death, which is essential for organismal homeostasis, exhibits multiple subroutines with different molecular mechanisms and signaling cascades. Within the expanding typology of regulated cell death pathways, ferroptosis is an iron-dependent non-apoptotic cell death caused by unrestrained lipid peroxidation culminating in irreversible plasma membrane damage. The basic process of ferroptosis involves the production of free radicals, the supply of fatty acids, and the increase in specialized enzymes (e.g., lipoxygenase [ALOX] and cytochrome P450 oxidoreductase [POR]) responsible for lipid peroxidation. More specifically, the oxidation of polyunsaturated fatty acids (PUFAs) appears to be a key driver of ferroptosis. Distinct types of PUFAs are associated with different risks of pathological conditions and diseases. Previous studies have shown that PUFAs are esterified into membrane phospholipids, especially phosphatidylethanolamine (PE)-containing phospholipids (arachidonic acid and adrenic acid), and then generate lipid peroxides, leading to ferroptosis in various cells or tissues. The acyl-CoA synthetase long-chain family member 4 (ACSL4)-lysophosphatidylcholine acyltransferase 3 (LPCAT3) pathway is responsible for the production of most PUFAs during ferroptosis. In contrast, the lipid peroxidation repair enzyme glutathione peroxidase 4 (GPX4) and the endosomal sorting complexes required for the transport (ESCRT)-III membrane repair machinery can prevent ferroptosis. Now, Zou et al. report that peroxisome-dependent plasmalogen production constitutes yet another, ACSL4/LPCAT3-independent phospholipid resource susceptible to ferroptotic oxidative damage in cancer cells, neurons, and cardiomyocytes (Fig. 1). In a first step, the authors performed genome-wide CRISPR–Cas9 suppressor screens to identify new genes that regulate the susceptibility of two tumor cell lines to GPX4 inhibitor (RSL3 and ML210)-induced ferroptosis: the clear cell renal cell carcinoma 786-O cell line and the human ovarian carcinoma OVCAR-8 cell line. This procedure led to a marked enrichment of peroxisome-related genes, the deletion of which increased cellular viability. Peroxisomes play multiple roles, including the production or elimination of hydrogen peroxide, the synthesis of certain lipids, and the degradation of long-chain and branched-chain fatty acids. Through the depletion or overexpression of peroxisome biogenesis genes (such as peroxisomal biogenesis factor 10 [PEX10] and PEX3), the authors found that the number of peroxisomes was positively correlated with susceptibility to ferroptosis. Therefore, peroxisomes may be added to the list of organelles that can initiate the ferroptotic cell death. Subsequently, the author explored how peroxisomes affect the sensitivity of cells to ferroptosis. Peroxisomal enzymes involved in the synthesis of plasmalogens, such as alkylglycerone phosphate synthase (AGPS), fatty acyl-CoA reductase 1 (FAR1), and glyceronephosphate O-acyltransferase (GNPAT), were significantly enriched among the CRISPR targets that confer cytoprotection. Lipidomic analysis revealed that the production of plasmalogens was diminished in PEX3or PEX10-deficient cells. These experiments indicate that peroxisomes affect the sensitivity of cells to ferroptosis by synthesizing plasmalogens, a subclass of ether phospholipids that are abundant in cell membranes in the cardiovascular, immune, and nervous systems. At difference with common phospholipids, plasmalogens use an ether (instead of an ester) bond to connect the glycerophospholipid. Their sn-1 chains are non-hydrolyzable ether-linked chains, while their sn-2 chains are connected by conventional ester bonds. Due to this special chemical structure, the synthesis of plasmalogen precursor needs to be carried out independently in the peroxisome. Here, the precursor 1-O-alkyl-glycerol-3-phosphate (AGP) is synthesized by FAR1 and AGPS and then transported to the endoplasmic reticulum (ER) for further biosynthetic reactions involving 1-acylglycerol-3phosphate O-acyltransferase 3 (encoded by AGPAT3). Finally, the ER-resident enzyme plasmanylethanolamine desaturase 1 (PEDS1, also known as TMEM189) mediates the production of PUFAplasmalogen. Importantly, the provision of liposomal nanoparticles composed of purified plasmalogens to cells was sufficient to confer sensitivity to ferroptosis by lipid peroxidation, further confirming the implication of plasmalogens in ferroptosis. Finally, the authors investigated the pathophysiological role of plasmalogen-dependent ferroptosis in disease-related scenarios. Unsurprisingly, human GPX4 knockout cancer cells inoculated into immunodeficient mice initially failed to strive, presumably due to an increase in the ferroptotic demise of the cells. However, after a latency period, mice carrying GPX4 cancer cells developed tumors that proliferated as quickly as GPX4-expressing parental cancer cells. Further lipidomics and genetic analysis showed that such GPX4 cells had not reacquired GPX4 expression and instead downregulated the synthesis of plasmalogens to become resistant against ferroptosis. In contrast, the differentiation of neuronal SY5Y precursors or cardiomyocytes derived from human induced pluripotent stem cells was associated with an increased sensitivity to ferroptosis induced by GPX4 inhibition, correlating with an increase in PUFA plasmalogens.

A TLR3 ligand reestablishes chemotherapeutic responses in the context of FPR1 deficiency

Abstract: For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor-1 (FPR1) on the surface of dendritic cells (DCs). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3 (TLR3), polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or that of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC and T lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared to wild type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.

Spermidine promotes mating and fertilization efficiency in model organisms

Abstract: Spermidine is a naturally occurring polyamine involved in multiple biological processes, including DNA metabolism, autophagy and aging. Like other polyamines, spermidine is also indispensable for successful reproduction at several stages. However, a direct influence on the actual fertilization process, i.e., the fusion of an oocyte with a spermatocyte, remains uncertain. To explore this possibility, we established the mating process in the yeast Saccharomyces cerevisiae as a model for fertilization in higher eukaryotes. During human fertilization, the sperm capacitates and the acrosome reaction is necessary for penetration of the oocyte. Similarly, sexually active yeasts form a protrusion called "shmoo" as a prerequisite for mating. In this study, we demonstrate that pheromone-induced shmoo formation requires spermidine. In addition, we show that spermidine is essential for mating in yeast as well as for egg fertilization in the nematode Caenorhabditis elegans. In both cases, this occurs independently from autophagy. In synthesis, we identify spermidine as an important mating component in unicellular and multicellular model organisms, supporting an unprecedented evolutionary conservation of the mechanisms governing fertilization-related cellular fusion.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Apoptosis: A Review of Programmed Cell Death

Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

The blockade of immune checkpoints in cancer immunotherapy

Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.