In eukaryotes, most proteins are degraded through one of the 2 major proteolytic pathways: the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Existing evidence suggests that these processes are critical to human physiology and pathology. Our study revealed a negative feedback system between proteasomal activity and autophagic flux in cells. We demonstrated that proteasome activation achieved by USP14 (ubiquitin specific peptidase 14) inhibition delays the fusion of autophagosomes with the lysosome. A new molecular circuit involving UVRAG (UV radiation resistance associated) was uncovered as a key linker between the systems, adding complexity to the regulatory crosstalk. These findings clearly demonstrate that the surveillance mechanisms for protein homeostasis and cell survival are not separate, but a coordinated system. We also found that proteasome activation promotes the clearance of MAPT (microtubule associated protein tau), while facilitating the aggregation of mutant HTT (huntingtin) in cells, indicating that the biochemical property of a protein might play a role in its response to degradation signals. Collectively, our results present novel mechanistic insights into the reciprocal communication between the UPS and autophagy, highlighting that while a strategy upregulating either the UPS or autophagy holds great potential, it may have caveats originating from the intrinsic feedback regulation between them.
Keywords: Autophagy; USP14; UVRAG; proteasome; proteopathy.