The transcriptional repressor PARIS, a substrate of the ubiquitin E3 ligase parkin, represses the expression of the transcriptional co-activator, PGC-1α gene, and is involved in several pathological processes, including neurodegenerative disease and cancers. We have previously shown that SUMOylation of PARIS play an important role in its transcriptional repression activity. In addition, RNF4-mediated ubiquitination of SUMO2/3-conjugated PARIS is required for the control of PARIS-mediated transcriptional repression in HeLa cells that lack parkin expression. However, little is known about how PARIS ubiquitination and degradation are regulated in parkin-deficient cells. Here, we report that the deSUMOylase SENP3 interacted with PARIS and enhanced the ubiquitination of PARIS independently of its SUMOylation in HeLa cells. SENP3-enhanced PARIS ubiquitination mainly contributed to its proteasomal degradation, and required the oncogenic E3 ubiquitin ligase MDM2. MDM2 knockdown by small interfering RNA or expression of a dominant-negative MDM2 mutant inhibited the ubiquitination of PARIS. We further found that MDM2 activation via the PI3K/AKT pathway was involved in PARIS ubiquitination. Taken together, these results suggest that PARIS ubiquitination through SENP3-mediated MDM2 activation may control its functions in parkin-deficient cells.
Keywords: E3 ubiquitin ligase; MDM2; Parkin interacting substrate (PARIS); SENP; SUMOylation; Ubiquitination.
Copyright © 2022 Elsevier Inc. All rights reserved.