KLHDC10

KLHDC10 is a kelch-repeat protein that functions both as an inhibitor of protein phosphatase 5 (PP5) and as a substrate receptor in the CRL2 E3 ubiquitin ligase complex. It binds the phosphatase domain of PP5 and suppresses its activity, thereby sustaining ROS-induced activation of the pro-apoptotic kinase ASK1 and promoting oxidative stress-induced cell death (PMID:23102700). As the substrate-recognition subunit of CRL2-KLHDC10, it directly recognizes C-terminal polyalanine (Ala-tail) degrons on aberrant nascent polypeptides produced during ribosome-associated quality control (RQC), targeting them for ubiquitylation and proteasomal degradation (PMID:37676773).

1. 2012 High

   Establishing KLHDC10 as a regulator of stress-induced apoptosis resolved how ROS-activated ASK1 signaling is sustained: KLHDC10 directly binds and inhibits PP5 phosphatase activity, preventing PP5-mediated dephosphorylation and inactivation of ASK1.

   Evidence Proteomics screen, reciprocal Co-IP, in vitro phosphatase assay, Drosophila genetic screen, and siRNA knockdown in mammalian Neuro2A cells

   PMID:23102700

   Open questions at the time

   • Structural basis of KLHDC10–PP5 interaction not determined
   • Whether KLHDC10 regulates PP5 substrates beyond ASK1 is unknown
   • Physiological relevance in mammalian tissues in vivo not established in this study
2. 2016 Medium

   Extending KLHDC10 function in vivo, knockout mice revealed that KLHDC10 deficiency selectively enhances necroptosis in inflammatory cells during TNFα-induced SIRS, dampening the cytokine response — demonstrating a role in modulating inflammatory cell death distinct from its ASK1-apoptosis axis.

   Evidence KLHDC10 knockout mouse model with TNFα-induced systemic inflammatory response syndrome and in vitro cell death assays

   PMID:27631783

   Open questions at the time

   • Molecular mechanism linking KLHDC10 to necroptosis pathway components (e.g., RIPK1/RIPK3/MLKL) not identified
   • Single-lab study; independent replication in additional inflammatory models lacking
   • Whether PP5 inhibition mediates the necroptosis phenotype was not tested
3. 2023 High

   Identification of KLHDC10 as the CRL2 substrate receptor for C-terminal polyalanine degrons established its role in ribosome-associated quality control — a function mechanistically distinct from its PP5 inhibition — and showed that the Ala-tail binding pocket evolved by repurposing a conserved C-degron recognition module.

   Evidence Biochemical binding assays, structure-guided mutagenesis of predicted Ala-tail binding pocket, and evolutionary sequence analysis

   PMID:37676773

   Open questions at the time

   • High-resolution experimental structure of KLHDC10 bound to an Ala-tail substrate not yet available
   • In vivo contribution of KLHDC10-mediated Ala-tail ubiquitylation to RQC pathway flux not quantified
   • Relationship between the two known functions (PP5 inhibition vs. CRL2 substrate receptor) is unresolved

• It remains unknown how the dual functions of KLHDC10 — PP5 inhibition in stress signaling and CRL2-mediated ubiquitylation in ribosome quality control — are coordinated or independently regulated in different cellular contexts.
• No structural data resolving whether PP5-binding and CRL2-adaptor surfaces overlap
• Tissue-specific regulation of the two functions is uncharacterized
• Mechanism linking KLHDC10 to necroptosis at the molecular level remains unidentified