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Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Academic Article
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Overview

authors

  • Sun, S.
  • Shi, G.
  • Han, X.
  • Francisco, A. B.
  • Ji, Y.
  • Mendonca, N.
  • Liu, X.
  • Locasale, J. W.
  • Simpson, K. W.
  • Duhamel, G. E.
  • Kersten, S.
  • Yates III, John
  • Long, Q.
  • Qi, L.

publication date

  • 2014

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L's physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 wk with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation, and promotes cell death. Serendipitously, using a biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of the mammalian Hrd1 ERAD complex and ER homeostasis, which is essential for protein translation, pancreatic function, and cellular and organismal survival.

subject areas

  • Animals
  • Atrophy
  • Cell Culture Techniques
  • Cell Death
  • Cell Proliferation
  • Cell Survival
  • Endoplasmic Reticulum
  • Endoplasmic Reticulum-Associated Degradation
  • Homeostasis
  • Mammals
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Pancreas, Exocrine
  • Polyribosomes
  • Protein Biosynthesis
  • Protein Stability
  • Proteins
  • Secretory Vesicles
  • Ubiquitin-Protein Ligases
  • Unfolded Protein Response
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Identity

PubMed Central ID

  • PMC3918815

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1318114111

PubMed ID

  • 24453213
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Additional Document Info

start page

  • E582

end page

  • E591

volume

  • 111

issue

  • 5

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