Fri, 11/08/2017 - 11:00
Campus SB, INM (Geb. D2 5), Leibniz-Saal

Prof. Kazuhiro Nagata
Host: Prof. Dr. Aranzazu del Campo
Laboratory of Molecular and Cellular Biology, Kyoto Sangyo University

Maintenance of ER homeostasis by ER redox network

Terminally misfolded secretory and membrane proteins are retro-translocated from the endoplasmic reticulum (ER) into the cytosol where they are degraded via ubiquitin-proteasome pathway, a process termed as ER-associated degradation (ERAD). We first identified a novel protein EDEM (ER-degradation enhancing a-mannosidase-like protein) and reported that EDEM recruits glycoproteins misfolded in the ER from synthetic pathways to degradation pathways in a mannose trimming-dependent manner.  We also found a novel protein ERdj5, an ER-resident disulfide reductase, as an EDEM-binding protein and identified its function playing a central role in ERAD by cleaving the disulfide bonds of the misfolded proteins that are recognized by EDEM.Recently, wefound that ERdj5 reduces the luminal disulfide bond of SERCA2b, a Ca2+-ATPase on the ER membrane, thereby activating its pump function. Notably, we found that ERdj5 activates SERCA2b at lower ER luminal [Ca2+] ([Ca2+]ER), while higher [Ca2+]ER induces ERdj5 to form oligomers that are no longer able to interact with the pump, suggesting [Ca2+]ER-dependent regulation. These results identify ERdj5 as a master regulator of ER calcium homeostasis, and thus shed light on the importance of crosstalk among redox, Ca2+ and protein homeostasis in the ER. We also found that the reductive force for RRdj5 is provided from the nascent polypeptide entering the ER via PDI/ERO1 system.  We will discuss on the molecular basis of this electron transfer pathway from nascent chains to ERdj5.

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