Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1

Joon No Lee, Jin Ye

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Insig-1 and Insig-2 are closely related proteins of the endoplasmic reticulum (ER) that block proteolytic activation of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells. When cellular cholesterol levels are high, Insig proteins bind to SREBP cleavage-activating protein, retaining it in the ER and preventing it from escorting SREBPs to the site of proteolytic activation in the Golgi complex. Here we report that hypotonic stress reverses the sterol-mediated inhibition of SREBP proteolytic activation by reducing the level of Insig-1 but not Insig-2. The reduction of Insig-1, a protein with a rapid turnover rate, results from a general inhibition of protein synthesis mediated by hypotonie stress. Insig-2 is not affected by hypotonie stress because of its slower turnover rate. Inhibition of protein synthesis by hypotonic shock has not been reported previously. Thapsigargin, an activator of the ER stress response, also inhibits protein synthesis and activates proteolysis of SREBP. Such activation also correlates with the disappearance of Insig-1. The current study demonstrates that animal cells, in response to either hypotonie shock or ER stress, can bypass the cholesterol inhibition of SREBP processing, an effect that is attributable to the rapid turnover of Insig-1.

Original languageEnglish (US)
Pages (from-to)45257-45265
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number43
DOIs
StatePublished - Oct 22 2004

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Sterol Regulatory Element Binding Proteins
Chemical activation
Proteins
Endoplasmic Reticulum Stress
Cholesterol
Osmotic Pressure
Endoplasmic Reticulum
Animals
Cells
Proteolysis
Thapsigargin
Golgi Apparatus
Sterols
Hypercholesterolemia
Shock
Transcription Factors
Fatty Acids
Membranes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. / Lee, Joon No; Ye, Jin.

In: Journal of Biological Chemistry, Vol. 279, No. 43, 22.10.2004, p. 45257-45265.

Research output: Contribution to journalArticle

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