The ATF3 Transcription Factor Is a Short-Lived Substrate of the Arg/N-Degron Pathway.

Biochemistry
Tri T M Vu, Alexander Varshavsky

Abstract

The Arg/N-degron pathway targets proteins for degradation by recognizing their specific N-terminal residues or, alternatively, their non-N-terminal degrons. In mammals, this pathway is mediated by the UBR1, UBR2, UBR4, and UBR5 E3 ubiquitin ligases, and by the p62 regulator of autophagy. UBR1 and UBR2 are sequelogous, functionally overlapping, and dominate the targeting of Arg/N-degron substrates in examined cell lines. We constructed, here, mouse strains in which the double mutant [UBR1-/- UBR2-/-] genotype can be induced conditionally, in adult mice. We also constructed human [UBR1-/- UBR2-/-] HEK293T cell lines that unconditionally lack UBR1/UBR2. ATF3 is a basic leucine zipper transcription factor that regulates hundreds of genes and can act as either a repressor or an activator of transcription. Using the above double-mutant mice and human cells, we found that the levels of endogenous, untagged ATF3 were significantly higher in both of these [UBR1-/- UBR2-/-] settings than in wild-type cells. We also show, through chase-degradation assays with [UBR1-/- UBR2-/-] and wild-type human cells, that the Arg/N-degron pathway mediates a large fraction of ATF3 degradation. Furthermore, we used split-ubiquitin and another protein int...Continue Reading

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Nov 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Tri T M VuAlexander Varshavsky

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