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ATF6 ubiquitylation is required for its transcriptional activity and degradation

ATF6α is an endoplasmic reticulum (ER) transmembrane protein that senses the accumulation of misfolded proteins in the ER of cells during ER stress. Upon ER stress, ATF6α is proteolytically cleaved. The resulting N‐terminal fragment becomes an active transcription factor, i.e. N‐ATF6α, which induces genes that adaptively reprogram ER protein folding. N‐ATF6α exerts potent but transient transcriptional activation of its target genes; the transient nature of its activity is due in part to its rapid degradation upon engagement in transcription. The transcriptional activation domain (TAD) and degradation domain (degron) of N‐ATF6α map to the same N‐terminal region of N‐ATF6α, implying that transcriptional activity and degradation are linked. Moreover, mutations introduced into the TAD of N‐ATF6α that decrease its activity also decrease its degradation, indicating that N‐ATF6α degradation is coupled with its transcriptional activity. To elucidate how and why N‐ATF6α degradation and activation are coupled, we examined the mechanism of N‐ATF6α degradation, positing that ubiquitylation may target it for proteasome‐mediated degradation. Accordingly, this study focused primarily on delineating whether N‐ATF6α is ubiquitylated, and if so, what domain(s) of N‐ATF6α are ubiquitylated, as well as investigating the functional consequences of such ubiquitylation.