TY - JOUR
T1 - Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1
AU - Lee, Joon No
AU - Ye, Jin
PY - 2004/10/22
Y1 - 2004/10/22
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M408235200
DO - 10.1074/jbc.M408235200
M3 - Article
C2 - 15304479
AN - SCOPUS:7244221504
SN - 0021-9258
VL - 279
SP - 45257
EP - 45265
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -