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Insig Regulates HMG‐CoA Reductase by a Non‐Degradative Mechanism in Fission Yeast
Author(s) -
Burg John S.,
Bard Martin,
Powell David W.,
Espenshade Peter J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a609-c
Subject(s) - reductase , sterol regulatory element binding protein , hmg coa reductase , yeast , microbiology and biotechnology , sumo protein , schizosaccharomyces pombe , chemistry , biochemistry , transcription factor , biology , ubiquitin , enzyme , saccharomyces cerevisiae , gene
The ER membrane protein Insig is a central regulator of the negative feedback control that regulates cholesterol homeostasis in mammalian cells. Insig controls the activity of HMG‐CoA reductase (HMGR), the enzyme that catalyzes the first committed step in sterol synthesis, by two distinct mechanisms. First, Insig downregulates HMGR transcription by retaining the transcription factor SREBP and its binding partner SCAP in the ER, thus preventing proteolytic activation of SREBP in the Golgi. Second, Insig accelerates degradation of HMGR by sterol‐dependent recruitment of ubiquitination machinery. Homologs of HMG‐CoA reductase, Insig, SREBP, and SCAP exist in the fission yeast S. pombe: hmg1+ , ins1+ , sre1+ , and scp1+ . Here, we report that fission yeast Insig forms a complex with Hmg1. Ins1 binding does not stimulate degradation of Hmg1, which is a stable protein. Rather, Ins1 inhibits Hmg1 by a degradation‐independent mechanism. Kinetic studies indicate that Ins1 is a non‐competitive inhibitor of Hmg1 activity, and sterol analysis suggests that Ins1 regulates HMG‐CoA reductase activity in vivo . Unlike mammals, Ins1 solely regulates Hmg1 insomuch as Ins1 does not interact with Scp1 or control Sre1 activation. Collectively, these data provide evidence for a third mechanism of HMGR regulation by Insig and raise the possibility that the original function of Insigs may have been to regulate HMGR. Research was funded by a grant from the NIH (HL‐077588) and a Burroughs Wellcome Fund Career Award in the Biomedical Sciences (PJE).