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.

The inositol trisphosphate receptor in the control of autophagy.

Abstract: The second messenger myo-inositol-1,4,5-trisphosphate (IP(3)) acts on the IP(3) receptor (IP(3)R), an IP(3)-activated Ca(2+) channel of the endoplasmic reticulum (ER). The IP(3)R agonist IP(3) inhibits starvation-induced autophagy. The IP(3)R antagonist xestospongin B induces autophagy in human cells through a pathway that requires the obligate contribution of Beclin-1, Atg5, Atg10, Atg12 and hVps34, yet is inhibited by ER-targeted Bcl-2 or Bcl-XL, two proteins that physically interact with IP(3)R. Autophagy can also be induced by depletion of the IP(3)R by small interfering RNAs. Autophagy induction by IP(3)R blockade cannot be explained by changes in steady state levels of Ca(2+) in the endoplasmic reticulum (ER) and the cytosol. Autophagy induction by IP(3)R blockade is effective in cells lacking the obligate mediator of ER stress IRE1. In contrast, IRE1 is required for autophagy induced by ER stress-inducing agents such a tunicamycin or thapsigargin. These findings suggest that there are several distinct pathways through which autophagy can be initiated at the level of the ER.

Metacaspases are caspases. Doubt no more.

Abstract: Caspases are cysteine proteases that cleave their substrates after an aspartate residue. Besides their multiple vital roles ranging from immune regulation to spermatogenesis, they are crucial in most cell death pathways, representing a sort of executing sword in the hands of apoptosis. In 2000, a psi-Blast in-silico approach led Uren et al. to identify two novel caspase-related families: metacaspases and paracaspases. Paracaspases are involved in the development of MALT lymphoma, but not in cell death execution, and are found both in eukaryotes owning caspases (animals), as well as in organisms lacking caspases. Metacaspases, on the other hand, are found only in eukaryotes that are devoid of caspases, for example, plants, protists and fungi. Similar to caspases, they contain a caspase-specific catalytic diad of histidine and cysteine, as well as a caspase-like secondary structure. Our lab was among the first to perform experiments on metacaspases showing that the sole metacaspase encoded by the genome of Saccharomyces cerevisiae (which we termed YCA1) is involved in oxidative stress-induced cell death. Overexpression of YCA1 caused a type of cell death that was accompanied by apoptotic markers, while deletion of YCA1 protected against apoptosis caused by reactive oxygen species or chronological aging. We thus had revealed that one metacaspase, YCA1, was involved in the same process as caspases, namely programmed cell death (PCD). Indeed, many groups subsequently unfolded the crucial contribution of metacaspases to cell death execution upon various stresses in yeast and other fungi, as well as in plants. Bozhkov, Zhivotovsky and colleagues could even demonstrate that the plant metacaspase mcII-Pa shapes the embryo of Norway spruce (Picea abies) during development, presumably through its implication in developmental cell death. Together with the unequivocal fact of a common evolutionary origin, these results made us conclude that, in functional terms, metacaspases behave like caspases, thus unchaining a stormy scientific debate. Driven by the fact that caspases occur in animals but metacaspases are present in all kingdoms except animals, many authors deduced that, although cell death is a universal and fundamental process, the implication of caspases in lethal processes is not necessarily conserved. The discovery that metacaspases have a different cleavage specificity than caspases – they hydrolyze proteins after arginine or lysine (basic residues), not after aspartate (an acidic residue) 7,9 – added further fuel to the discussion. In fact, the exclusion of metacaspases from the caspase family and their regrouping into a separate family in the CD clan of cysteine peptidases was demanded. In other words, it was implicated that metacaspases are not caspases. Nevertheless, we strongly felt that Yca1p, a protein that possesses sequence homology to human caspases, and the knockout of which rescues roughly 40% of all cell death scenarios tested in yeast, should retain the name ‘metacaspase’. Nomenclature reaches beyond particular points of divergence (such as localization, structural features or, as it is for metacaspases, the amino acid specificity) when it refers to functional groups. For instance, we use the expression ‘nucleic acids’ for DNA or RNA from prokaryotes that by definition lack nuclei. Similarly, we talk about ‘mitochondrial DNA’ even though this pool of DNA is located in the mitochondria, not in the nucleus. Admittedly, the question whether metacaspases are caspases (or not) can only be answered by enzymology rather than by the vague comparison of their implication in various lethal signaling pathways. Do caspases and metacaspases cleave similar death-related substrates? We reasoned that, although a major divergence of the amino acid specificity of caspases and metacaspases may have occurred during evolution, their target proteins should fall into similar functional groups if the role of caspases and metacaspases was conserved. Hence, do the degradomes of caspases and metacaspases overlap? In a recent paper published in Nature Cell Biology, Peter Bozhkov and colleagues identified the first metacaspase substrate, which they showed to be a functional substrate of mammalian caspase-3 as well. In their seminal study, they demonstrated that both caspases and metacaspases cleave the phylogenetically conserved protein TSN (Tudor staphylococcal nuclease). The authors revealed that TSN from P. abies (PaTSN) is cleaved by its metacaspase (mcII-Pa) at four different sites. This process was blocked either by adding a metacaspase inhibitor or by mutation of a catalytic cysteine. Importantly, PaTSN was shown to be a component of the degradome during both stress-induced and developmental PCD. During embryogenesis, metacaspase activity correlated with proteolysis of endogenous PaTSN in the different embryo stages (high in early and low in mature embryos). Consistently, knockdown of mcII-Pa via

Endonuclease G mediates α‐synuclein cytotoxicity during Parkinson's disease

Abstract: Malfunctioning of the protein α-synuclein is critically involved in the demise of dopaminergic neurons relevant to Parkinson's disease. Nonetheless, the precise mechanisms explaining this pathogenic neuronal cell death remain elusive. Endonuclease G (EndoG) is a mitochondrially localized nuclease that triggers DNA degradation and cell death upon translocation from mitochondria to the nucleus. Here, we show that EndoG displays cytotoxic nuclear localization in dopaminergic neurons of human Parkinson-diseased patients, while EndoG depletion largely reduces α-synuclein-induced cell death in human neuroblastoma cells. Xenogenic expression of human α-synuclein in yeast cells triggers mitochondria-nuclear translocation of EndoG and EndoG-mediated DNA degradation through a mechanism that requires a functional kynurenine pathway and the permeability transition pore. In nematodes and flies, EndoG is essential for the α-synuclein-driven degeneration of dopaminergic neurons. Moreover, the locomotion and survival of α-synuclein-expressing flies is compromised, but reinstalled by parallel depletion of EndoG. In sum, we unravel a phylogenetically conserved pathway that involves EndoG as a critical downstream executor of α-synuclein cytotoxicity.

ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy

Abstract: Tumor cells succumb to chemotherapy while releasing ATP We have found that extracellular ATP attracts dendritic cell (DC) precursors into the tumor bed, facilitates their permanence in the proximity of dying cells and promotes their differentiation into mature DCs endowed with the capacity of presenting tumor-associated antigens

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.