title: A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1.
abstract: Disturbances in the normal functions of the endoplasmic reticulum (ER) can lead to the accumulation of unfolded proteins and disturbance of Ca(2+) regulation within the lumen of ER, and arouse a series of complicated response termed unfolded protein response (UPR), which is aimed initially at reestablishing homeostasis and normal physiology but can ultimately trigger cell death if the UPR fails to compensate for damage. Here we show that ER locating human RING finger E3 ligase RNF186 participates in the process of ER stress-mediated apoptosis. Overexpression of RNF186 stimulates upregulation of ER sensor proteins and rapid transmission of ER Ca(2+) in Hela cells, while RNF186 knockdown exhibits a moderate degree of resistance to ER stress, indicating RNF186 can arouse stress signaling at ER. We further identified the Bcl-2 family protein BNip1 as one of the substrates of RNF186. BNip1 co-localizes with RNF186 at ER and is poly-ubiquitinated by RNF186 through K29 and K63 linkage in vivo. This modification promotes BNip1 transportation to mitochondria but has no influence on its protein level. The half-life of RNF186 is prolonged under ER stress, probably because of the inhibition on its self-ubiquitination and subsequent degradation by proteasomes. In addition, the ubiquitination of BNip1 is greatly enhanced when ER stress occurred, possibly due to RNF186 accumulation. More importantly, knockdown of BNip1 attenuates the stress signals at ER induced by RNF186. These results collectively indicate that BNip1 functions as a downstream modulator of RNF186 to direct ER stress-associated apoptotic signaling. Our study might reveal a novel E3 ligase-mediated mechanism for modulating ER stress.
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China. wps85920@gmail.com
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jiyan
authors.initials: J
authors.lastname: Zheng
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054829:RING Finger Domains; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C119020:BNIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C587047:RNF186 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D002118:Calcium
keywords: BNip1; Ca(2+) release; Endoplasmic reticulum stress; RNF186; Ubiquitination