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An Increase in Expression of the ER Stress Responsive Protein IRE1α Occurs in Response to the Anti‐HIV Drug Efavirenz in Primary Human Hepatocytes.
Author(s) -
VanAusdall Jennifer Lynn,
Bumpus Namandje
Publication year - 2013
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.27.1_supplement.890.19
Subject(s) - unfolded protein response , atf6 , endoplasmic reticulum , efavirenz , protein kinase r , downregulation and upregulation , calnexin , reverse transcriptase , protein kinase a , biology , microbiology and biotechnology , chemistry , kinase , biochemistry , human immunodeficiency virus (hiv) , immunology , rna , calreticulin , cyclin dependent kinase 2 , antiretroviral therapy , gene , viral load
Efavirenz (EFV), one of the most commonly prescribed drugs for HIV, has been associated with liver toxicity; however the mechanism( s) for this is not well understood. In non‐stressed conditions, BiP (binding immunoglobulin protein) binds IRE1α (inositol‐requiring enzyme 1α), PERK (PKR‐like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6), rendering them inactive. BiP dissociates when ER stress is sensed, allowing these proteins to become activated. Immunoblotting revealed that primary human hepatocytes treated with 10μM of EFV expressed IRE1α at a 3‐fold increase at 6 hours, while no significant expression changes were observed at 3 and 24 hour time points. A commensurate increase in IRE1α mRNA levels was observed using reverse transcriptase PCR. The chaperone proteins calnexin and grp94, whose expression is upregulated by ER stress, demonstrated modest increases (1.5 fold) after 6 hours of EFV treatment, as did BiP (1.5 fold). No significant change in expression was observed in PERK or ATF6 with EFV treatment. Interestingly, results obtained from human samples were not recapitulated in primary mouse hepatocytes, despite being a conserved pathway, indicating a possible species difference. The results above suggest that EFV may exert its effects through the IRE1α pathway specifically, not by inducing the global unfolded protein response.