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Ubiquitylation of the er-stress transciption factor ATF6 alpha
Aivati, Cathrine Maheen
Glembotski, Christopher C.
Bennet, Eric J.
Lin, Jonathan H.
Sohl, Christal D.
Zayas, Ricardo M.
ATF6α is an endoplasmic reticulum (ER) transmembrane protein that senses misfolded proteins in the ER. During ER stress, ATF6α is proteolytically cleaved. The resulting N-terminal fragment is an active transcription factor, N-ATF6α, which induces genes that restore ER protein folding. N-ATF6α exerts potent, transient transcriptional activation of its target genes. This is due in part to its rapid degradation upon engagement in transcription. N-ATF6α transcriptional activation domain (TAD) and degradation domain (degron) map to the same N-terminal region, implying that both are linked. Mutations made in 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. This study focused on delineating whether N-ATF6α is ubiquitylated, and if so, what domain(s) of N-ATF6α are ubiquitylated, and investigating the functional consequences of such ubiquitylation.
San Diego State University
Doctor of Philosophy (Ph.D.) University of California, San Diego and San Diego State University, 2018
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