Modulating cellular balance of Rps3 mono-ubiquitination by both Hel2 E3 ligase and Ubp3 deubiquitinase regulates protein quality control

Abstract

When a ribosome complex is stalled during the translation elongation process in eukaryotes, the mono-ubiquitination of Rps3 has recently been shown to be critical to ribosome quality control. We have discovered that the regulatory role of Rps3 mono-ubiquitination is controlled by a deubiquitinase. We also showed that an autophagic signal appears to be coupled to the mono-ubiquitination of Rps3p through the entrance of Ubp3p into the autophagosome in yeasts. The mono-ubiquitination of the Rps3 protein is tightly modulated by reciprocal action between the Hel2p E3 ligase and the Ubp3p deubiquitinase in yeasts and the reciprocal action between the RNF123 E3 ligase and the USP10 deubiquitinase in mammalian cells. We also found that the Ubp3p/USP10 deubiquitinases critically modulate Hel2p/RNF123-mediated Rps3p mono-ubiquitination. In addition, we found that Hel2p/RNF123 and Ubp3p/USP10 appeared to be differently localized in the ribosome complex after ultraviolet irradiation. Together, our results support a model in which coordinated ubiquitination and deubiquitination activities can finely balance the level of regulatory Rps3p mono-ubiquitination in ribosome-associated quality control and autophagy processes.

Cracking the Monoubiquitin Code of Genetic Diseases

“…Because carbohydrate transporters are plasma membrane proteins, this finding is consistent with previous studies linking down-regulation of membrane receptors to monoubiquitination-mediated endocytosis [5]. The stability of ribosomal and proteasomal subunits is also regulated by monoubiquitination [6]. Multi-monoubiquitination could also act as a degradation signal [7].…”

Chaperone-E3 Ligase Complex HSP70-CHIP Mediates Ubiquitination of Ribosomal Protein S3

“…Previous studies showed that monoubiquitination of RPS3 by Asc1 (RACK1 in mammals) or Hel2 is required for ribosome-associated quality control [ 19 , 31 ] but does not cause proteasomal degradation of RPS3. Although treatment with the HSP90 inhibitor elicited UPS-dependent degradation of RPS3, recruiting HSP70 [ 18 ], the identity of the E3 ligase responsible for RPS3 degradation and its biological significance have not been reported.…”

DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery

“…USP10 also plays a critical role in protein quality control by regulating the monoubiquitination of Rsp3 (30). Misfolded proteins, a potential intracellular toxic species, are recognized by chaperones and eliminated from cellular environment broadly by the ubiquitin-proteasome system.…”

“…It has previously been reported that ubiquitination of ribosomal proteins regulates the ribosomal quality control (RQC) activity. During active translation, Rsp3 is monoubiquitinated by the Hel3p/RNF123 E3 ligase (30). It is well established that the temporal stalling of the ribosome during translation activates RQC pathways.…”