Premium
The Role of Arv1 in Sterol Metabolism and its Contribution to the Unfolded Protein Response
Author(s) -
Shechtman Caryn Faith,
Henneberry Annette,
Seimon Tracie,
Tabas Ira,
Sturley Stephen L
Publication year - 2010
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.24.1_supplement.845.4
Subject(s) - unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , downregulation and upregulation , sterol , gene knockdown , lipid metabolism , endoplasmic reticulum associated protein degradation , chemistry , mutant , biology , biochemistry , apoptosis , cholesterol , gene
Proper sterol distribution within the cell is a critical component of membrane homeostasis. The endoplasmic reticulum (ER)‐localized protein Arvl mediates sterol transport from the ER to the plasma membrane. Alterations in ER sterol distribution are a stimulus for unfolded protein response (UPR) activation. We hypothesize that the loss of Arv1p in yeast will increase the free sterol (FS) content of the ER, resulting in UPR induction. The UPR will also be induced in primary murine macrophages where ARV1 expression has been knocked down. Loss of yeast Arv1p function results activation of the UPR, mediated by Ire1p. The yeast arv1Δ ire1Δ homozygous haploid is inviable. Mutant ire1 core luminal domains, defective in sensing unfolded proteins, rescue the lethality of the arv1Δ ire1Δ haploid; these strains exhibited increased UPR induction that was synergistic with protein misfolding. We also demonstrate that decreased ARV1 expression in mammalian cells results in UPR induction, particularly an upregulation of CHOP. As a result of ARV1 knockdown, macrophages undergo apoptosis due to prolonged UPR induction and FS‐induced cytotoxicity. We demonstrate that defects in ER homeostasis, as a result of changes in ARV1 expression, exhibit UPR induction in both yeast and mammalian systems. The UPR appears to be a generalized response, resulting from perturbations in membrane structure, lipid metabolism and protein folding.