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  • The EMBO Journal (2005) 24, 3917 - 3926
  • doi:10.1038/sj.emboj.7600855

Published online: 3 November 2005

INSIG: a broadly conserved transmembrane chaperone for sterol-sensing domain proteins

Isabelle Flury1,a, Renee Garza1, Alexander Shearer1, Johanna Rosen1,b, Stephen Cronin1 and Randolph Y Hampton1

  1. Section of Cell and Development Biology, UCSD Division of Biological Sciences, La Jolla, CA, USA

Correspondence to:

Randolph Y Hampton, Section of Cell and Development Biology, UCSD Division of Biological Sciences, 9500 Gilman Dr, La Jolla, CA 92093, USA. Tel.: +1 858 822 0511/0512; Fax: +1 858 534 0555; E-mail: rhampton@ucsd.edu

aPresent address: Baslerstrasse 252, Allschwil, Switzerland

bPresent address: University of Virginia School of Medicine, Richmond, VA, USA

Received 17 March 2005; Accepted 6 October 2005

INSIGs are proteins that underlie sterol regulation of the mammalian proteins SCAP (SREBP cleavage activating protein) and HMG-CoA reductase (HMGR). The INSIGs perform distinct tasks in the regulation of these effectors: they promote ER retention of SCAP, but ubiquitin-mediated degradation of HMGR. Two questions that arise from the discovery and study of INSIGs are: how do they perform these distinct tasks, and how general are the actions of INSIGs in biology? We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. Nsg1p functions naturally to limit degradation of Hmg2p when both proteins are at native levels, indicating a long-standing functional interplay between these two classes of proteins. One way to unify the known, disparate actions of INSIGs is to view them as known adaptations of a chaperone dedicated to SSD-containing client proteins.

  • Keywords:

    • ERAD,
    • HMG-CoA reductase,
    • HRD genes,
    • INSIG,
    • sterol-sensing domain