Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

FEBS Letters

article

Kana Otsubo¹  Chiaki Maeyashiki¹  Yoichi Nibe¹  Akiko Tamura¹  Emi Aonuma¹  Hiroki Matsuda¹  Masanori Kobayashi¹  Michio Onizawa¹  Yasuhiro Nemoto¹  Takashi Nagaishi²  Ryuichi Okamoto³  Kiichiro Tsuchiya¹  Tetsuya Nakamura⁴  Satoru Torii⁵  Eisuke Itakura⁶  Mamoru Watanabe¹  Shigeru Oshima¹ 

[1] Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University;Department of Advanced Therapeutics for GI Diseases, Tokyo Medical and Dental University;Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University;Department of Research and Development for Organoids, Juntendo University School of Medicine;Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University;Department of Biology, Graduate school of Science, Chiba University;Advanced Research Institute, Tokyo Medical and Dental University

关键词: autophagy;    necroptotic stimulation;    necrostatin-1;    RIPK3;    SQSTM1/p62;    STX17;   

DOI  :  10.1002/1873-3468.13748

来源: John Wiley & Sons Ltd.

【 摘 要 】

Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-a plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome–lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis.

【 授权许可】

Unknown