CONTROL OF STRESS RESPONSES BY VIRAL AND CELLULAR BASIC LEUCINE ZIPPER TRANSCRIPTION FACTORS

Abstract

Glycoproteins are processed through the secretory pathway and require folding in the endoplasmic reticulum (ER). When unfolded proteins accumulate in the ER, the sensor protein ATF6 is activated, translocated to the Golgi, and proteolytically processed into ATF6-N, a member of the heterodimerizing family of basic leucine zipper (bZIP) transcription factors. ATF6-N restores proteostasis by upregulating chaperones and ER-associated degradation genes. Kaposi’s sarcoma-associated herpesvirus (KSHV) activates ATF6 cleavage but suppresses the downstream production of antiviral effectors. I hypothesized that ATF6-N is antiviral and KSHV must subvert its antiviral activity. Indeed, I showed that ectopically expressed ATF6-N reduces viral titers. I investigated if K-bZIP, a viral bZIP and multifunctional transcriptional repressor essential for viral replication, is an inhibitor of ATF6, but found that K-bZIP does not perturb ATF6-N signaling. Conversely, ATF6-N impairs nuclear import of K-bZIP. I concluded that ATF6-N is antiviral to KSHV, but the mechanism of action remains unknown.