Necroptosis activates UPR sensors without disrupting their binding with GRP78


Posted: 2021-09-21 19:00:00
Proc Natl Acad Sci U S A . 2021 Sep 28;118(39):e2110476118. doi: 10.1073/pnas.2110476118. Wei Liang 1 , Weiwei Qi 1 2 , Yang Geng 1 , Linhan Wang 1 2 , Jing Zhao 1 2 , Kezhou Zhu 1 , Guowei Wu 1 2 , Zairong Zhang 1 , Heling Pan 1 , Lihui Qian 1 , Junying Yuan 3 Affiliations Expand Affiliations 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China. 2 University of Chinese Academy of Sciences, Beijing 100049, China. 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; junying_yuan@sioc.ac.cn. Item in Clipboard Wei Liang et al. Proc Natl Acad Sci U S A. 2021. Show details Display options Display options Format Proc Natl Acad Sci U S A . 2021 Sep 28;118(39):e2110476118. doi: 10.1073/pnas.2110476118. Authors Wei Liang 1 , Weiwei Qi 1 2 , Yang Geng 1 , Linhan Wang 1 2 , Jing Zhao 1 2 , Kezhou Zhu 1 , Guowei Wu 1 2 , Zairong Zhang 1 , Heling Pan 1 , Lihui Qian 1 , Junying Yuan 3 Affiliations 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China. 2 University of Chinese Academy of Sciences, Beijing 100049, China. 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; junying_yuan@sioc.ac.cn. Item in Clipboard CiteDisplay options Display options Format Abstract Necroptosis is a form of regulated necrosis mediated by the formation of the necrosome, composed of the RIPK1/RIPK3/MLKL complex. Here, we developed a proximity ligation assay (PLA) that allows in situ visualization of necrosomes in necroptotic cells and in vivo. Using PLA assay, we show that necrosomes can be found in close proximity to the endoplasmic reticulum (ER). Furthermore, we show that necroptosis activates ER stress sensors, PERK, IRE1α, and ATF6 in a RIPK1-RIPK3-MLKL axis-dependent manner. Activated MLKL can be translocated to the ER membrane to directly initiate the activation of ER stress signaling. The activation of IRE1α in necroptosis promotes the splicing of XBP1, and the subsequent incorporation of spliced XBP1 messenger RNA (mRNA) into extracellular vesicles (EVs). Finally, we show that unlike that of a conventional ER stress response, necroptosis promotes the activation of unfolded protein response (UPR) sensors without affecting their binding of GRP78. Our study reveals a signaling pathway that links MLKL activation in necroptosis to an unconventional ER stress response. Keywords: ER stress; IRE1α; PERK; UPR sensors; necroptosis. Conflict of interest statement The authors declare no competing interest. References Shan B., Pan H., Najafov A., Yuan J.. Necroptosis in development and diseases. Genes Dev.. 2018;32:327–340. Wallach D., Kang T. B., Dillon C. P., Green D. R.. Programmed necrosis in inflammation: Toward identification of the effector molecules. Science. 2016;352:aaf2154. Fulda S.. The mechanism of necroptosis in normal and cancer cells. Cancer Biol. Ther.. 2013;14:999–1004. Sun L., et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–227. Degterev A., et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol.. 2008;4:313–321. Show all 33 references

参考サイト PubMed: exsome


Powered by Kreditvergleich


バイオクイックニュース日本語版:エクソソーム特集

バイオクイックニュース日本語版
7月 03, 2021 バイオアソシエイツ

エクソソームを用いた血液検査でパーキンソン病と多系統萎縮症の識別に成功

UCLAヘルスの研究者らは、パーキンソン病と多系統萎縮症(MSA)というよく似た2つの運動障害を見分けることができる血液検査を開発した。この検査法は、脳細胞から送り出されて血液中に混入する「 エクソソーム 」と呼ばれる微小な小胞の内容物を分析することで、パーキンソン病を識別するもので、現在は研究用に限定されている。 今回の研究成果は、2021年5月15日付でActa…

ゲスト 834人 と メンバー 4人 がオンラインです