Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer’s disease, Parkinson’s disease and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor Enhancer Lin12 1 Like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.
Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality / A.B. Francisco, R. Singh, S. Li, A.K. Vani, L. Yang, R.J. Munroe, G. Diaferia, M. Cardano, I. Biunno, L. Qi, J.C. Schimenti, Q. Long. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 285:18(2010 Apr 30), pp. 13694-13703.
|Titolo:||Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality|
|Parole Chiave:||unfolded protein response ; ubiquitin ligase complex ; cell-death program ; quality-control ; secretory pathway ; messenger-RNA ; tumor-growth ; ER stress ; degradation ; expression|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore BIO/10 - Biochimica
|Data di pubblicazione:||30-apr-2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1074/jbc.M109.085340|
|Appare nelle tipologie:||01 - Articolo su periodico|