DCAF10

DCAF10 is a WD40-repeat substrate receptor (N-recognin) of the CUL4A-DDB1 cullin-RING E3 ubiquitin ligase that selects diverse cytoplasmic proteins for ubiquitin-mediated proteasomal degradation (PMID:41484149). Its defining biochemical activity is recognition of N-terminally acetylated Src-family kinases through an N-terminal acetyl-glycine degron, allowing DCAF10 to monitor the switch from N-terminal myristoylation to acetylation and to direct mis-acetylated kinases to the reconstituted CUL4A-DDB1-DCAF10 complex for ubiquitination (PMID:41484149). Through this same ligase architecture, DCAF10 drives degradation of additional substrates with distinct physiological consequences: it is stabilized by the deubiquitinase OTUD1 to degrade MCL1 and activate caspase-dependent apoptosis (PMID:33898171), and it degrades cytoplasm-translocated ALOX15B following ABHD17C-driven depalmitoylation in KRAS-mutant pancreatic cancer (PMID:40569151). The complex is also subverted by adenovirus E1A, which binds DCAF10 to assemble a CUL4 ligase that destroys RUVBL1/2, blocks IRF3 activation, and suppresses antiviral interferon-stimulated gene expression (PMID:37962355).

1. 2021 Medium

   Established that DCAF10 acts as a functional substrate receptor within the CUL4A-DDB1 ligase and that its own stability is controlled by deubiquitination, linking it to apoptotic control via MCL1 turnover.

   Evidence Co-immunoprecipitation, deubiquitination and degradation assays with apoptosis readouts showing OTUD1 stabilizes DCAF10 to degrade MCL1

   PMID:33898171

   Open questions at the time

   • No in vitro reconstitution or DCAF10 mutagenesis defining the MCL1 recognition interface
   • Degron determinant on MCL1 not identified
2. 2023 Medium

   Revealed that DCAF10 can be hijacked by a viral effector to redirect CUL4 ligase activity against host innate-immune machinery, defining a pathogen-exploited substrate-recruitment route.

   Evidence Adenovirus E1A binding and CUL4 complex assembly with RUVBL1/2 degradation and IRF3/ISG functional readouts

   PMID:37962355

   Open questions at the time

   • Structural basis of E1A-DCAF10 interaction not resolved
   • Whether RUVBL1/2 are endogenous DCAF10 substrates absent E1A is unclear
3. 2025 Medium

   Extended the DCAF10 substrate range to a lipid-modified enzyme, showing that loss of a membrane-anchoring acyl modification creates a cytoplasmic pool recognized by the ligase, tying DCAF10 to ferroptosis evasion.

   Evidence Co-IP of ALOX15B with CUL4/DDB1/DCAF10, depalmitoylation and proteasome-rescue assays, organoid and in vivo tumor models

   PMID:40569151

   Open questions at the time

   • Direct degron on ALOX15B not mapped
   • No reconstituted ubiquitination of ALOX15B by the complex
4. 2026 High

   Defined the molecular logic of DCAF10 substrate selection by identifying it as an N-recognin reading an N-terminal acetyl-glycine degron, establishing a quality-control role over lipidation-versus-acetylation status of Src-family kinases.

   Evidence Peptide pull-downs, mass spectrometry, AlphaFold 3 predictions, CRISPR/siRNA perturbation, and in vitro reconstituted ubiquitination of N-acetylated SFKs

   PMID:41484149

   Open questions at the time

   • Experimental high-resolution structure of the DCAF10-degron complex not determined
   • Full breadth of endogenous N-acetyl-degron substrates beyond SFKs unknown

• It remains unresolved whether DCAF10's diverse substrates (SFKs, MCL1, ALOX15B, RUVBL1/2) share a unifying recognition principle or whether distinct degron classes are read by the same WD40 receptor.
• No comparison of degron features across the reported substrates
• Regulatory inputs governing substrate choice in different cell contexts not defined