The C‐degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes

Abstract

Protein termini are determinants of protein stability. Proteins bearing degradation signals, or degrons, at their amino-or carboxyl-termini are eliminated by the Nor C-degron pathways, respectively. We aimed to elucidate the function of C-degron pathways and to unveil how normal proteomes are exempt from C-degron pathway-mediated destruction. Our data reveal that C-degron pathways remove mislocalized cellular proteins and cleavage products of deubiquitinating enzymes. Furthermore, the C-degron and N-degron pathways cooperate in protein removal. Proteome analysis revealed a shortfall in normal proteins targeted by C-degron pathways, but not of defective proteins, suggesting proteolysis-based immunity as a constraint for protein evolution/ selection. Our work highlights the importance of protein termini for protein quality surveillance, and the relationship between the functional proteome and protein degradation pathways.

CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

“…Among DCAF12 potential substrates, proteins localizing to the cytoplasm, mitochondria, or secretory pathway were significantly enriched. This suggests that beyond the regulation of cytoplasmic proteins, DCAF12 might also contribute, together with other C-terminal degron pathways [71], to elimination of secretory or mitochondrial proteins mislocalized to the cytoplasm.…”

How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

“…The resultant N- and C-terminal fragments are targeted for proteasomal degradation by CRL2 KLHDC2 and UBR1 E3s, respectively ( Lin et al., 2018 ; Piatkov et al., 2012 ; Ravalin et al., 2021 ; Rusnac et al., 2018 ). Moreover, products of other deubiquitylases that generate N-terminal fragments terminating with diGly/C-degrons are also targeted by CRL2 KLHDC2 ( Yeh et al., 2021 ).…”

“…Truncated polypeptides terminating with Gly/ or ArgXXGly/C-degrons bind CRL2 substrate receptors, such as KLHDC2/3 or APPBP2, which direct ubiquitin-mediated clearance. Interestingly, Gly is the least abundant C-terminal residue in properly translated eukaryotic proteins, but it is very commonly produced by translation errors, suggesting a general role of the Gly/C-degron pathway in ensuring quality control for the eukaryotic proteome ( Koren et al., 2018 ; Lin et al., 2018 ; Timms and Koren, 2020 ; Yeh et al., 2021 ).…”

Post-translational Modifications of the Protein Termini

“…Such C-degrons are grouped into three different groups, including full length proteins, C-termini generated by cleavage, and prematurely terminated products ( Lin et al, 2018 ; Varshavsky, 2019 ). A detailed characterization of C-degrons and related functional pathways are yet to determined ( Yeh et al, 2021 ). It appears likely that other intracellular mechanisms could contribute to this pathway.…”