Michael Karin

Bio: Michael Karin is an academic researcher from University of California, San Diego. The author has contributed to research in topics: IκB kinase & Signal transduction. The author has an hindex of 236, co-authored 704 publications receiving 226485 citations. Previous affiliations of Michael Karin include Sanford-Burnham Institute for Medical Research & University of California, Los Angeles.

Emerging roles of Lys63-linked polyubiquitylation in immune responses.

Abstract: Among all the E2 ubiquitin-conjugating enzymes, Ubc13, which heterodimerizes with Uev1a, specifically mediates lysine 63 (K63)-linked protein polyubiquitylation, a process that does not lead to proteasomal degradation of its substrates. Instead, it plays a key role in signal transduction. Numerous roles of Lys63-linked polyubiquitylation in immune responses have emerged, indicating the importance of this regulatory strategy. Here, we summarize some of the signaling pathways that depend on Lys63-linked polyubiquitylation during innate and adaptive immune responses, with a focus on the underlying molecular mechanisms. In addition, we describe how Ubc13 itself is regulated and outline its function in transforming growth factor β signaling. We discuss the current progress in pharmacological targeting of Ubc13 in inflammatory and autoimmune diseases as well as cancer therapy.

Transcriptional regulation of the Th17 immune response by IKKα

Abstract: Th17 cells are a subset of T cells that play crucial roles in the pathogenesis of many inflammatory diseases. We report here the identification of IKKα (inhibitor of NF-κB kinase-α) as a key transcriptional regulator of the Th17 lineage. T cells expressing a nonactivatable form of IKKα were significantly compromised in their ability to produce IL-17 and to initiate neural inflammation. IKKα is present in the nuclei of resting CD4+ T cells. Upon Th17 differentiation, IKKα selectively associated with the Il17a locus, and promoted its histone H3 phosphorylation and transcriptional activation in a NF-κB–independent manner. These findings indicate that nuclear IKKα maintains the Th17 phenotype by activating the Il17a gene.

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.

Abstract: Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

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。

REACTIVE OXYGEN SPECIES: Metabolism, Oxidative Stress, and Signal Transduction

Abstract: Several reactive oxygen species (ROS) are continuously produced in plants as byproducts of aerobic metabolism. Depending on the nature of the ROS species, some are highly toxic and rapidly detoxified by various cellular enzymatic and nonenzymatic mechanisms. Whereas plants are surfeited with mechanisms to combat increased ROS levels during abiotic stress conditions, in other circumstances plants appear to purposefully generate ROS as signaling molecules to control various processes including pathogen defense, programmed cell death, and stomatal behavior. This review describes the mechanisms of ROS generation and removal in plants during development and under biotic and abiotic stress conditions. New insights into the complexity and roles that ROS play in plants have come from genetic analyses of ROS detoxifying and signaling mutants. Considering recent ROS-induced genome-wide expression analyses, the possible functions and mechanisms for ROS sensing and signaling in plants are compared with those in animals and yeast.