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CHIP controls necroptosis through ubiquitylation- and lysosome-dependent degradation of RIPK3
Seo, Jinho,Lee, Eun-Woo,Sung, Hyerim,Seong, Daehyeon,Dondelinger, Yves,Shin, Jihye,Jeong, Manhyung,Lee, Hae-Kyung,Kim, Jung-Hoon,Han, Su Yeon,Lee, Cheolju,Seong, Je Kyung,Vandenabeele, Peter,Song, Jae Nature Publishing Group 2016 NATURE CELL BIOLOGY Vol. No.
<P>Receptor-interacting protein kinase 3 (RIPK3) functions as a key regulator of necroptosis. Here, we report that the RIPK3 expression level is negatively regulated by CHIP (carboxyl terminus of Hsp70-interacting protein; also known as STUB1) E3 ligase-mediated ubiquitylation. Chip(-/-) mouse embryonic fibroblasts and CHIP-depleted L929 and HT-29 cells exhibited higher levels of RIPK3 expression, resulting in increased sensitivity to necroptosis induced by TNF (also known as TNF alpha). These phenomena are due to the CHIP-mediated ubiquitylation of RIPK3, which leads to its lysosomal degradation. Interestingly, RIPK1 expression is also negatively regulated by CHIP-mediated ubiquitylation, validating the major role of CHIP in necrosome formation and sensitivity to TNF-mediated necroptosis. Chip(-/-) mice (C57BL/6) exhibit inflammation in the thymus and massive cell death and disintegration in the small intestinal tract, and die within a few weeks after birth. These phenotypes are rescued by crossing with Ripk3(-/-) mice. These results imply that CHIP is a bona fide negative regulator of the RIPK1-RIPK3 necrosome formation leading to desensitization of TNF-mediated necroptosis.</P>
The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics
Seo, Jinho,Kim, Min Wook,Bae, Kwang-Hee,Lee, Sang Chul,Song, Jaewhan,Lee, Eun-Woo Elsevier 2019 Biochemical pharmacology Vol.162 No.-
<P><B>Abstract</B></P> <P>Regulation of cell survival and death, including apoptosis and necroptosis, is important for normal development and tissue homeostasis, and disruption of these processes can cause cancer, inflammatory diseases, and degenerative diseases. Ubiquitination is a cellular process that induces proteasomal degradation by covalently attaching ubiquitin to the substrate protein. In addition to proteolytic ubiquitination, nonproteolytic ubiquitination, such as M1-linked and K63-linked ubiquitination, has been shown to be important in recent studies, which have demonstrated its function in cell signaling pathways that regulate inflammation and cell death pathways. In this review, we summarize the TRAIL- and TNF-induced death receptor signaling pathways along with recent advances in this field and illustrate how different types of ubiquitination control cell death and survival. In particular, we provide an overview of the different types of ubiquitination, target residues, and modifying enzymes, including E3 ligases and deubiquitinating enzymes. Given the relevance of these regulatory pathways in human disease, we hope that a better understanding of the regulatory mechanisms of cell death pathways will provide insights into and therapeutic strategies for related diseases.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
New role of E3 ubiquitin ligase in the regulation of necroptosis
( Jinho Seo ),( Eun-woo Lee ),( Jaewhan Song ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.5
Necroptosis is a well-known form of caspase-independent cell death. Necroptosis can be triggered by various extrinsic stimuli, including death ligands in the presence of receptorinteracting protein kinase 3 (RIPK3), a key mediator of necroptosis induction. Our recent studies have revealed that C-terminus HSC-70 interacting protein (CHIP), an E3 ligase, can function as an inhibitor of necroptosis. CHIP-/- mouse embryonic fibroblast showed higher sensitivity to necrotic stimuli than wild-type mouse embryonic fibroblast cells. Deleterious effects of CHIP knockout MEFs were retrieved by RIPK3 depletion. We found that CHIP negatively regulated RIPK3 and RIPK1 by ubiquitylation- and lysosome- dependent degradation. In addition, CHIP-/- mice showed postnatal lethality with intestinal defects that could be rescued by crossing with RIPK3-/- mice. These results suggest that CHIP is a negative regulator of RIPK1 and RIPK3, thus inhibiting necroptosis. [BMB Reports 2016; 49(5): 247-248]
Necroptosis molecular mechanisms: Recent findings regarding novel necroptosis regulators
Seo Jinho,Nam Young Woo,Kim Seongmi,Oh Doo-Byoung,Song Jaewhan 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-
Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic phenotypes, including swelling and membrane rupture, and release damage-associated molecular patterns (DAMPs), inflammatory cytokines, and chemokines, thereby mediating extreme inflammatory responses. Studies on gene knockout or necroptosis-specific inhibitor treatment in animal models have provided extensive evidence regarding the important roles of necroptosis in inflammatory diseases. The necroptosis signaling pathway is primarily modulated by activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates mixed-lineage kinase domain-like protein (MLKL), mediating MLKL oligomerization. In the necroptosis process, these proteins are fine-tuned by posttranslational regulation via phosphorylation, ubiquitination, glycosylation, and protein–protein interactions. Herein, we review recent findings on the molecular regulatory mechanisms of necroptosis.
주거비 부담능력이 부족한 민간임차가구 규모는 얼마인가?
서진호(Jinho Seo),김지환(Jihwan Kim),진창하(Changha Jin) 한국주택학회 2022 주택연구 Vol.30 No.1
The purpose of this study is to examine rental housing affordability to verify the determinant for rental housing affordability. Furthermore we measure the relative marginal change of overall demand of affordable housing as we adopt a standard of living from advanced countries such as U.K. and Japan. Using Residual Income Approach and Housing Quality Approach, we measure the number of total 1.5 million household are in need of affordable housing policy. Also we measure total 0.41 million household are counted as a group necessary for affordable housing policy. The income effect has positive impact on this measure which implies an increased income in each household decreases a possibility to be in a group necessary for affordable housing policy. If we assume a standard of living from advanced countries such as UK, and Japan, the percentage of group necessary for affordable housing policy has increased by 3% and 6%, respectively. We conclude that it is important to specifically measure the rental housing affordability in order to provide a necessary various affordable housing policy.