The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
DCAF10 (also known as WDR32) is a human gene encoding a DDB1- and CUL4-associated factor 10 protein (UniProt ID: Q5QP82). The protein belongs to the WD repeat DCAF10 family and contains characteristic WD40 repeat domains that fold into a β-propeller structure (kremer2026cul4addb1dcaf10isan pages 1-2). DCAF10 is evolutionarily conserved, with homologs identified across mammalian species (mistry2020expressionprofilingof pages 1-2).
DCAF10 functions as a substrate receptor (specificity factor) for Cullin 4-RING E3 ubiquitin ligase (CRL4) complexes, comprising CUL4A (or CUL4B), DDB1, DCAF10, and the catalytic subunit RBX1 (kremer2026cul4addb1dcaf10isan pages 1-2, zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 5-7). As a substrate receptor, DCAF10 recruits specific target proteins to the E3 ligase complex, facilitating their ubiquitination and subsequent proteasomal degradation (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 6-8). The interaction between DCAF10 and the CRL4 scaffold requires DDB1 as an adaptor protein; DCAF10 binds DDB1 through conserved WDxR motifs within its WD40 repeats (zemke2023adenoviruse1abinding pages 5-7).
Recent breakthrough research by Kremer et al. (2026) identified DCAF10 as an N-recognin for proteins bearing N-terminally acetylated glycine (Ac-Gly) residues, particularly those that normally undergo N-myristoylation (kremer2026cul4addb1dcaf10isan pages 1-2). This discovery defines a novel N-degron pathway termed the "Ac-Gly/MO (myristoylation-omitted) N-degron pathway" (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 8-9).
Structural Basis of Recognition:
AlphaFold 3 predictions combined with biochemical validation demonstrate that DCAF10 recognizes Ac-Gly through a deep pocket within its β-propeller structure (kremer2026cul4addb1dcaf10isan pages 2-3, kremer2026cul4addb1dcaf10isan pages 3-4). The acetyl group of the N-terminal glycine is critical for high-affinity binding; specific DCAF10 residues including Phe172, Asn215, Lys257, Ile475, and Glu477 interact with the Ac-Gly moiety and are highly conserved across species (kremer2026cul4addb1dcaf10isan pages 3-4). Additional sequence features influence binding affinity: hydrophobic residues at positions 3-4 of the substrate strengthen interaction, while acidic residues at positions 5-7 weaken binding (kremer2026cul4addb1dcaf10isan pages 2-3, kremer2026cul4addb1dcaf10isan pages 3-4).
Substrate Specificity:
The recognition motif is not simply Ac-Gly but includes downstream residues, with a preference for serine at position 6 and lysine at position 7 (kremer2026cul4addb1dcaf10isan pages 2-3). This selectivity distinguishes proteins targeted by DCAF10 from those that are robustly acetylated but not degraded, such as THOC7, which contains acidic residues (Asp6-Asp7-Glu8) that repel DCAF10's negatively charged pocket environment (kremer2026cul4addb1dcaf10isan pages 2-3, kremer2026cul4addb1dcaf10isan pages 3-4).
| Substrate | Recognition Motif/Mechanism | Post-translational Modification Requirement | Biological Context/Function | Citation |
|---|---|---|---|---|
| Lyn (Src family kinase) | Direct recognition by DCAF10 of an N-terminal acetylated glycine (Ac-Gly) degron in a DCAF10 β-propeller pocket; binding is favored by sequence features near positions 3-4 and weakened by acidic residues at positions 5-7; full-length Lyn interacts with DCAF10 and is directly ubiquitinated by reconstituted CUL4A-DDB1-DCAF10 | Requires initiator methionine removal and N-terminal acetylation of Gly2; becomes especially relevant when N-myristoylation is reduced or absent; Gly2 identity is critical, as G2A/G2P mutants strongly reduce DCAF10-dependent ubiquitination | Quality-control degradation of improperly N-myristoylated Src-family kinases; regulates Lyn abundance and links cotranslational N-terminal modification state to proteasomal turnover | (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 4-5, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9) |
| Fyn (Src family kinase) | Direct DCAF10 binding to acetylated N-terminus, analogous to Lyn; robust pull-down with acetylated peptide and direct ubiquitination by reconstituted CUL4A-DDB1-DCAF10 | Requires an N-terminal acetylated Gly2; effect is enhanced under NMT1/2 depletion, consistent with competition between myristoylation and acetylation/failure states | Controls Fyn turnover when N-myristoylation fails, acting in an Ac-Gly/N-degron-like surveillance pathway parallel to ZYG11B/ZER1-mediated Gly/N-degron control | (kremer2026cul4addb1dcaf10isan pages 2-3, kremer2026cul4addb1dcaf10isan pages 4-5, kremer2026cul4addb1dcaf10isan pages 6-8) |
| Src (Src family kinase) | DCAF10 recognizes acetylated Src N-terminus more weakly/shallowly than Lyn or Fyn, but still supports DCAF10-dependent ubiquitination in vitro and increased Src abundance after DCAF10 depletion | Requires N-terminal processing compatible with Ac-Gly recognition; dependence on the canonical Ac-Gly pocket appears weaker than for Lyn/Fyn, suggesting additional or shallower binding contacts | Extends DCAF10 surveillance to Src-family signaling proteins, potentially buffering aberrant non-myristoylated Src species | (kremer2026cul4addb1dcaf10isan pages 2-3, kremer2026cul4addb1dcaf10isan pages 4-5, kremer2026cul4addb1dcaf10isan pages 6-8) |
| RUVBL1/2 | Identified in DCAF10 immunoprecipitates; adenoviral E1A promotes assembly of a DCAF10-containing CRL4 complex that targets RUVBL1/2 for proteasomal degradation | No specific substrate PTM requirement was defined for DCAF10 recognition in this context; degradation depends on Cullin-RING ligase activity and viral E1A-assisted CRL4 assembly | Loss of RUVBL1/2 suppresses IRF3 stabilization and interferon-stimulated gene activation, linking DCAF10 to innate immune control, multiprotein-machine assembly, and stress-response pathways | (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 5-7, zemke2023adenoviruse1abinding pages 7-11) |
| ALOX15B | DCAF10 binds depalmitoylated ALOX15B and promotes its association with DDB1/CUL4A; AlphaFold/co-IP mapping supports interaction between the ALOX15B N-terminal region and the DCAF10 WD40 region; DCAF10 promotes K48-linked ubiquitination and degradation | Requires prior ABHD17C-mediated depalmitoylation; mutation of ALOX15B C106 or blockade of depalmitoylation alters DCAF10 association; K175 in ALOX15B is implicated as a key ubiquitin-acceptor site | In KRAS-mutant pancreatic ductal adenocarcinoma, DCAF10-dependent ALOX15B degradation contributes to ferroptosis evasion and tumor progression | (li2025krasabhd17calox15baxispromotes pages 6-8) |
| IRF3 (indirect) | DCAF10 depletion increases IRF3 protein without increasing IRF3 mRNA, but IRF3 was not detected as a direct DCAF10 interactor; current evidence supports indirect regulation, likely through DCAF10-dependent degradation of upstream factors such as RUVBL1/2 in the adenoviral system | No direct PTM-dependent recognition by DCAF10 has been demonstrated; effect depends on DCAF10 and Cullin-based ligase function in infected or uninfected epithelial cells | Negative regulation of innate immunity and interferon-stimulated gene expression; exploited by adenovirus to blunt antiviral responses | (zemke2023adenoviruse1abinding pages 2-5, zemke2023adenoviruse1abinding pages 5-7, zemke2023adenoviruse1abinding pages 7-11) |
Table: This table summarizes the best-supported DCAF10 substrates and substrate-like targets, highlighting how DCAF10 recognizes them, what post-translational states are required, and the biological contexts in which these interactions matter. It is useful for separating direct DCAF10 substrates from cases, such as IRF3, where the evidence currently supports indirect regulation.
The most extensively characterized DCAF10 substrates are Src family kinases—Lyn, Fyn, and Src—which normally require N-myristoylation for membrane localization and proper function (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9). When N-myristoylation by NMT1/2 is impaired or absent, these proteins can be alternatively N-terminally acetylated by NatA, generating an Ac-Gly N-terminus that DCAF10 recognizes (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 5-6, kremer2026cul4addb1dcaf10isan pages 4-5).
Experimental Evidence:
- Peptide pull-down assays using mass spectrometry identified DCAF10 as the primary binder to acetylated Lyn, Fyn, and Src N-terminal peptides (kremer2026cul4addb1dcaf10isan pages 2-3).
- In vitro ubiquitination assays with reconstituted CUL4A-DDB1-DCAF10 complexes directly ubiquitinated immunoprecipitated Lyn, Fyn, and Src proteins (kremer2026cul4addb1dcaf10isan pages 6-8).
- DCAF10 knockdown increased Lyn, Fyn, and Src protein levels, particularly when NMT1/2 was depleted, without affecting mRNA levels (kremer2026cul4addb1dcaf10isan pages 5-6, kremer2026cul4addb1dcaf10isan pages 4-5).
- Cycloheximide chase experiments showed accelerated degradation of SFKs upon NMT1/2 depletion, which was reversed by proteasome inhibitor MG132 (kremer2026cul4addb1dcaf10isan pages 4-5).
Functional Context:
DCAF10-mediated degradation acts complementarily to the CUL2-elonginB/C-ZYG11B/ZER1 Gly/N-degron pathway, which recognizes free (non-acetylated) N-terminal glycine (kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9). This dual surveillance system ensures proteostasis control over SFKs that fail proper N-myristoylation. Mutation of the N-terminal glycine to alanine (G2A, which can be acetylated) or proline (G2P, which resists acetylation) confirmed that both glycine identity and acetylation are required for DCAF10-dependent degradation (kremer2026cul4addb1dcaf10isan pages 8-9).
RUVBL1 and RUVBL2 (also known as Pontin and Reptin) are essential AAA+ ATPases that function as subunits of multiple protein complexes, including HSP90 co-chaperones and chromatin-modifying complexes (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11). These proteins are required for assembly of multiprotein machines involved in DNA repair, transcriptional responses to interferon, and metabolic stress responses (zemke2023adenoviruse1abinding pages 7-11).
Evidence for DCAF10 Targeting:
Co-immunoprecipitation studies identified RUVBL1/2 as DCAF10-interacting proteins (zemke2023adenoviruse1abinding pages 7-11). In the context of adenovirus infection, viral protein E1A binds DCAF10 and promotes assembly of a functional CRL4 E3 ligase complex that targets RUVBL1/2 for degradation (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 5-7, zemke2023adenoviruse1abinding pages 7-11). Depletion of RUVBL1/2 prevented IRF3 stabilization induced by inhibition of EP300/CREBBP acetyltransferases, positioning RUVBL1/2 as critical mediators of innate immune responses that DCAF10 can negatively regulate (zemke2023adenoviruse1abinding pages 7-11).
In KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), DCAF10 mediates degradation of ALOX15B, a lipoxygenase enzyme involved in ferroptosis induction (li2025krasabhd17calox15baxispromotes pages 6-8).
Mechanistic Details:
ALOX15B degradation by DCAF10 requires prior depalmitoylation by the enzyme ABHD17C (li2025krasabhd17calox15baxispromotes pages 6-8). When ALOX15B is S-palmitoylated at Cys106, it localizes to the membrane and is protected from degradation. ABHD17C-mediated depalmitoylation promotes ALOX15B translocation to the cytoplasm and enhances its interaction with DCAF10 (li2025krasabhd17calox15baxispromotes pages 6-8). AlphaFold 3 analysis predicted that the N-terminal region of ALOX15B (residues N183-R221) docks with the central WD40 repeat region of DCAF10 (residues E188-S318), and this interaction was confirmed experimentally with a binding affinity (KD) of 6.96 nM (li2025krasabhd17calox15baxispromotes pages 6-8). The CUL4/DDB1/DCAF10 complex ubiquitinates ALOX15B at lysine 175 (K175), promoting its proteasomal degradation (li2025krasabhd17calox15baxispromotes pages 6-8).
Interferon regulatory factor 3 (IRF3) is stabilized when DCAF10 is depleted, leading to increased expression of interferon-stimulated genes (ISGs) (zemke2023adenoviruse1abinding pages 2-5, zemke2023adenoviruse1abinding pages 7-11). However, IRF3 was not detected in direct DCAF10 immunoprecipitates, suggesting indirect regulation (zemke2023adenoviruse1abinding pages 5-7). Current evidence indicates that DCAF10 controls IRF3 levels indirectly through degradation of RUVBL1/2, which are required for IRF3 stabilization (zemke2023adenoviruse1abinding pages 7-11).
DCAF10 functions in both nuclear and cytoplasmic compartments as part of the ubiquitin-proteasome system (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 5-7). The protein interacts with nuclear proteins including transcription factors and chromatin-associated proteins, while also regulating cytoplasmic substrates such as Src family kinases (kremer2026cul4addb1dcaf10isan pages 1-2, zemke2023adenoviruse1abinding pages 1-2). DCAF10's ability to assemble with CUL4A/B-DDB1 allows it to function wherever these scaffold proteins localize, providing flexibility to access substrates in different cellular compartments (zemke2023adenoviruse1abinding pages 5-7).
| Biological Process/Pathway | DCAF10 Role | Molecular Mechanism | Physiological Significance | Disease Association |
|---|---|---|---|---|
| N-degron pathway (Ac-Gly/MO branch) | Substrate receptor in a CUL4A-DDB1-DCAF10 E3 ubiquitin ligase; proposed N-recognin for N-terminally acetylated glycine degrons | Directly binds Ac-Gly N-termini, especially on typically myristoylated proteins; recognition is strengthened by favorable residues near positions 3-4 and weakened by acidic residues around positions 5-7; promotes ubiquitination and proteasomal turnover of substrates such as Lyn/Fyn/Src when myristoylation is reduced or omitted (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 4-5, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9) | Provides proteostasis surveillance over proteins that fail proper co-translational N-myristoylation, complementing the ZYG11B/ZER1 Gly/N-degron branch (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9) | Potential relevance to disorders involving aberrant N-terminal processing or proteostasis; mechanistically linked to oncogenic Src-family kinase control (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9) |
| Src kinase signaling | Negative regulator of Src-family kinase abundance under conditions of impaired N-myristoylation | DCAF10 recognizes and promotes ubiquitination of Lyn, Fyn, and Src; in vitro reconstituted CUL4A-DDB1-DCAF10 ubiquitinates these kinases, and DCAF10 depletion stabilizes them, especially after NMT1/2 knockdown (kremer2026cul4addb1dcaf10isan pages 5-6, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9) | Limits accumulation of misprocessed SFKs and may fine-tune membrane signaling capacity by coupling N-terminal modification state to protein stability (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9) | Strong relevance to cancer biology because SFKs are major oncogenic signaling proteins (kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 8-9) |
| Innate immunity / IRF3-ISG axis | Suppressor of IRF3 protein accumulation and interferon-stimulated gene activation in epithelial cells | DCAF10 knockdown increases IRF3 protein without increasing IRF3 mRNA, indicating post-transcriptional control; in adenovirus infection, DCAF10 participates in a CRL4 complex assembled by E1A that indirectly prevents IRF3 stabilization, at least in part through targeting RUVBL1/2 (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11) | Dampens antiviral transcriptional responses and shapes the threshold for ISG induction (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11) | Relevant to host antiviral defense and viral immune evasion (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11) |
| Viral infection (adenovirus E1A hijacking) | Hijacked host substrate receptor used by adenovirus E1A to assemble a functional CRL4 ligase complex | WT adenovirus e1a binds DCAF10, promotes association with DDB1 and CUL4A/B, and enables degradation of e1a itself and RUVBL1/2; this suppresses the late interferon response triggered by E1A-mediated inhibition of EP300/CREBBP acetyltransferases (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 2-5, zemke2023adenoviruse1abinding pages 5-7, zemke2023adenoviruse1abinding pages 7-11) | Enhances viral replication by blunting host innate immune signaling and remodeling host proteostasis machinery (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 2-5, zemke2023adenoviruse1abinding pages 7-11) | Human adenovirus respiratory infection / viral pathogenesis (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 2-5, zemke2023adenoviruse1abinding pages 7-11) |
| RUVBL1/2-dependent stress and immune regulation | Likely substrate-selecting factor for degradation of RUVBL1/2 in the adenoviral context | RUVBL1/2 co-immunoprecipitate with DCAF10; their abundance increases when DCAF10-dependent viral complex formation is disrupted; RUVBL1/2 are required for IRF3 stabilization after EP300/CREBBP inhibition, placing DCAF10 upstream of this stress/immune node (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11) | Connects DCAF10 to assembly/stability of multiprotein machines involved in antiviral defense, DNA damage/stress responses, and chaperone-dependent complex biogenesis (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11) | Relevant to infection biology and possibly broader stress-response phenotypes (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 7-11) |
| Testicular development / spermatogenesis | Probable regulatory DCAF with high testis expression, suggesting specialized reproductive functions | DCAF10 is a WD40/DCAF family member predicted to function as a CRL4 substrate receptor; transcript profiling found Dcaf10 among genes with highest expression in testis, with marked enrichment relative to other tissues in mouse and human datasets (mistry2020expressionprofilingof pages 5-9, mistry2020expressionprofilingof pages 2-4, mistry2020expressionprofilingof pages 1-2) | Suggests a role in germ-cell development, ubiquitin-dependent remodeling, or protein quality control during spermatogenesis, though direct substrate-level evidence in testis remains limited (mistry2020expressionprofilingof pages 5-9, mistry2020expressionprofilingof pages 2-4, mistry2020expressionprofilingof pages 1-2) | Candidate relevance to male fertility / testicular biology (mistry2020expressionprofilingof pages 5-9, mistry2020expressionprofilingof pages 2-4, mistry2020expressionprofilingof pages 1-2) |
| Cancer (pancreatic; ferroptosis evasion) | Promotes degradation of ALOX15B as part of a CUL4/DDB1/DCAF10 ligase axis | Depalmitoylation of ALOX15B by ABHD17C facilitates ALOX15B-DCAF10 interaction; DCAF10 supports association of ALOX15B with DDB1/CUL4A and promotes ubiquitin-dependent degradation, including K48-linked polyubiquitination, lowering ALOX15B and favoring ferroptosis evasion (li2025krasabhd17calox15baxispromotes pages 6-8) | Links DCAF10 to lipid metabolism, membrane-state sensing, and suppression of ferroptotic tumor restraint pathways (li2025krasabhd17calox15baxispromotes pages 6-8) | KRAS-mutant pancreatic ductal adenocarcinoma progression and therapy resistance biology (li2025krasabhd17calox15baxispromotes pages 6-8) |
Table: This table summarizes the main biological processes and pathways currently linked to human DCAF10, emphasizing its role as a CRL4 substrate receptor in proteostasis, signaling, immunity, reproduction, viral infection, and pancreatic cancer.
DCAF10 defines a novel branch of the N-degron pathway that monitors N-terminal co-translational modifications (kremer2026cul4addb1dcaf10isan pages 1-2). When proteins fail to receive their proper N-terminal modification—particularly myristoylation—they expose alternative N-termini that serve as degradation signals (degrons). The Ac-Gly/MO pathway mediated by DCAF10 complements the established Gly/N-degron pathway (mediated by ZYG11B/ZER1), creating redundant quality control over N-terminally misprocessed proteins (kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9).
DCAF10 plays a complex role in innate immune regulation. Under normal conditions or during viral infection, DCAF10-mediated degradation of RUVBL1/2 suppresses IRF3 accumulation and limits expression of interferon-stimulated genes (ISGs) (zemke2023adenoviruse1abinding pages 2-5, zemke2023adenoviruse1abinding pages 7-11). Human adenovirus exploits this mechanism: the viral E1A protein binds DCAF10 and promotes assembly of an active CRL4 complex that degrades RUVBL1/2, thereby blunting antiviral responses and facilitating viral replication (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 5-7, zemke2023adenoviruse1abinding pages 7-11).
Src family kinases are critical signaling molecules implicated in cancer progression and cellular transformation (kremer2026cul4addb1dcaf10isan pages 1-2). By degrading improperly N-myristoylated SFKs, DCAF10 may serve as a tumor suppressor mechanism that limits accumulation of delocalized, potentially oncogenic kinases (kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9). Conversely, dysregulation of DCAF10 could contribute to altered SFK signaling in disease contexts.
Expression profiling studies demonstrate remarkably high DCAF10 expression in testis compared to other tissues. Analysis of mouse and human RNA-seq datasets revealed that approximately 74-83% of DCAF subfamily genes, including DCAF10, are predominantly or specifically expressed in testis (mistry2020expressionprofilingof pages 5-9, mistry2020expressionprofilingof pages 2-4). DCAF10 shows highest transcript levels in testis with very low expression in other tissues, suggesting a specialized role in spermatogenesis (mistry2020expressionprofilingof pages 5-9). During testicular development, DCAF10 expression is upregulated during post-natal stages from neonatal day 20 through adulthood, coinciding with active spermatogenesis (mistry2020expressionprofilingof pages 5-9). This pattern implicates DCAF10 in germ cell development and suggests that ubiquitin-dependent protein remodeling by DCAF10 may be critical for male reproductive biology (mistry2020expressionprofilingof pages 1-2).
In KRAS-mutant pancreatic ductal adenocarcinoma, the KRAS/ERK1 signaling axis promotes ABHD17C-mediated depalmitoylation of ALOX15B, facilitating its DCAF10-dependent degradation (li2025krasabhd17calox15baxispromotes pages 6-8). Since ALOX15B promotes ferroptosis (a form of regulated cell death driven by lipid peroxidation), its degradation allows cancer cells to evade ferroptotic death, promoting tumor progression (li2025krasabhd17calox15baxispromotes pages 6-8). This mechanism highlights DCAF10 as a potential therapeutic target in KRAS-mutant PDAC.
The most significant recent advance in DCAF10 biology is the identification of its role as an N-recognin for N-terminally acetylated glycine residues by Kremer et al. (2026, Nature Communications) (kremer2026cul4addb1dcaf10isan pages 1-2). This work employed peptide pull-downs, quantitative mass spectrometry, AlphaFold 3 structural predictions, and in vitro reconstitution of the CUL4A-DDB1-DCAF10 E3 ligase to demonstrate direct substrate recognition and ubiquitination (kremer2026cul4addb1dcaf10isan pages 2-3, kremer2026cul4addb1dcaf10isan pages 3-4, kremer2026cul4addb1dcaf10isan pages 1-2, kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9).
Zemke et al. (2023, Journal of Virology) revealed how adenovirus hijacks DCAF10 to manipulate host innate immunity, demonstrating that the viral E1A protein recruits DCAF10 into a CRL4 complex that degrades RUVBL1/2, thereby suppressing interferon responses (zemke2023adenoviruse1abinding pages 1-2, zemke2023adenoviruse1abinding pages 5-7, zemke2023adenoviruse1abinding pages 7-11).
Li et al. (2025, Advanced Science) identified DCAF10's role in KRAS-driven pancreatic cancer, showing that the KRAS/ABHD17C/ALOX15B axis promotes ferroptosis evasion through DCAF10-mediated ALOX15B degradation (li2025krasabhd17calox15baxispromotes pages 6-8).
The discovery of DCAF10 as an Ac-Gly N-recognin fundamentally expands our understanding of N-degron pathways. While N-terminal acetylation is generally considered a protective modification that prevents degradation, DCAF10 demonstrates that acetylation can also create context-dependent degrons (kremer2026cul4addb1dcaf10isan pages 1-2). This dual role emphasizes the complexity of N-terminal processing and its integration with proteostasis networks.
The complementary surveillance by DCAF10 (recognizing Ac-Gly) and ZYG11B/ZER1 (recognizing free Gly) ensures robust quality control over proteins that fail N-myristoylation, preventing accumulation of mislocalized proteins that could disrupt cellular functions (kremer2026cul4addb1dcaf10isan pages 6-8, kremer2026cul4addb1dcaf10isan pages 8-9). This redundancy underscores the importance of proper co-translational modification for cellular homeostasis.
The tissue-specific expression pattern of DCAF10, particularly its high abundance in testis, suggests that this protein may have specialized substrates in male germ cells that remain to be identified (mistry2020expressionprofilingof pages 5-9, mistry2020expressionprofilingof pages 2-4, mistry2020expressionprofilingof pages 1-2). Further research is needed to characterize DCAF10's specific role in spermatogenesis and whether defects in DCAF10 contribute to male infertility.
DCAF10 is a substrate receptor for CUL4A-DDB1 E3 ubiquitin ligase complexes that recognizes N-terminally acetylated glycine degrons, particularly on proteins that normally undergo N-myristoylation. Its primary substrates include Src family kinases (Lyn, Fyn, Src), RUVBL1/2 AAA+ ATPases, and ALOX15B. DCAF10 functions in protein quality control, innate immune regulation, cell signaling, testicular development, and is implicated in viral immune evasion and cancer progression. The protein localizes to both nuclear and cytoplasmic compartments and exhibits particularly high expression in testis. Recent structural and biochemical studies have defined the molecular basis of DCAF10's substrate recognition through a β-propeller pocket that binds Ac-Gly with sequence-specific constraints. These advances position DCAF10 as a critical regulator of proteostasis and a potential therapeutic target in cancer and infectious diseases.
Key Citations:
- Kremer et al., 2026, Nature Communications, DOI: 10.1038/s41467-025-68074-9
- Zemke et al., 2023, Journal of Virology, DOI: 10.1128/jvi.00993-23
- Li et al., 2025, Advanced Science, DOI: 10.1002/advs.202504470
- Mistry et al., 2020, BMC Genomics, DOI: 10.1186/s12864-020-07016-9
References
(kremer2026cul4addb1dcaf10isan pages 1-2): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(mistry2020expressionprofilingof pages 1-2): Bhavesh V. Mistry, Maha Alanazi, Hanae Fitwi, Olfat Al-Harazi, Mohamed Rajab, Abdullah Altorbag, Falah Almohanna, Dilek Colak, and Abdullah M. Assiri. Expression profiling of wd40 family genes including ddb1- and cul4- associated factor (dcaf) genes in mice and human suggests important regulatory roles in testicular development and spermatogenesis. BMC Genomics, Aug 2020. URL: https://doi.org/10.1186/s12864-020-07016-9, doi:10.1186/s12864-020-07016-9. This article has 32 citations and is from a peer-reviewed journal.
(zemke2023adenoviruse1abinding pages 1-2): Nathan R. Zemke, Emily Hsu, William D. Barshop, Jihui Sha, James A. Wohlschlegel, and Arnold J. Berk. Adenovirus e1a binding to dcaf10 targets proteasomal degradation of ruvbl1/2 aaa+ atpases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress. Journal of Virology, Dec 2023. URL: https://doi.org/10.1128/jvi.00993-23, doi:10.1128/jvi.00993-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(zemke2023adenoviruse1abinding pages 5-7): Nathan R. Zemke, Emily Hsu, William D. Barshop, Jihui Sha, James A. Wohlschlegel, and Arnold J. Berk. Adenovirus e1a binding to dcaf10 targets proteasomal degradation of ruvbl1/2 aaa+ atpases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress. Journal of Virology, Dec 2023. URL: https://doi.org/10.1128/jvi.00993-23, doi:10.1128/jvi.00993-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(kremer2026cul4addb1dcaf10isan pages 6-8): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kremer2026cul4addb1dcaf10isan pages 8-9): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kremer2026cul4addb1dcaf10isan pages 2-3): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kremer2026cul4addb1dcaf10isan pages 3-4): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kremer2026cul4addb1dcaf10isan pages 4-5): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(zemke2023adenoviruse1abinding pages 7-11): Nathan R. Zemke, Emily Hsu, William D. Barshop, Jihui Sha, James A. Wohlschlegel, and Arnold J. Berk. Adenovirus e1a binding to dcaf10 targets proteasomal degradation of ruvbl1/2 aaa+ atpases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress. Journal of Virology, Dec 2023. URL: https://doi.org/10.1128/jvi.00993-23, doi:10.1128/jvi.00993-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(li2025krasabhd17calox15baxispromotes pages 6-8): Man Li, Xuexin Yu, Yuanji Liu, Shuqin Ouyang, Long Wu, Xiaohong Chen, Huiqi Yu, Haoming Chen, Senmao Lian, Ziwen Li, Liyun Gong, Libing Song, and Jun Li. Kras/abhd17c/alox15b axis promotes pancreatic cancer progression via ferroptosis evasion. Advanced science, pages e04470, Jun 2025. URL: https://doi.org/10.1002/advs.202504470, doi:10.1002/advs.202504470. This article has 8 citations and is from a peer-reviewed journal.
(zemke2023adenoviruse1abinding pages 2-5): Nathan R. Zemke, Emily Hsu, William D. Barshop, Jihui Sha, James A. Wohlschlegel, and Arnold J. Berk. Adenovirus e1a binding to dcaf10 targets proteasomal degradation of ruvbl1/2 aaa+ atpases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress. Journal of Virology, Dec 2023. URL: https://doi.org/10.1128/jvi.00993-23, doi:10.1128/jvi.00993-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(kremer2026cul4addb1dcaf10isan pages 5-6): Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S. Robles, Andrea Musacchio, and Tanja Bange. Cul4a-ddb1-dcaf10 is an n-recognin for n-terminally acetylated src kinases. Nature Communications, Jan 2026. URL: https://doi.org/10.1038/s41467-025-68074-9, doi:10.1038/s41467-025-68074-9. This article has 2 citations and is from a highest quality peer-reviewed journal.
(mistry2020expressionprofilingof pages 5-9): Bhavesh V. Mistry, Maha Alanazi, Hanae Fitwi, Olfat Al-Harazi, Mohamed Rajab, Abdullah Altorbag, Falah Almohanna, Dilek Colak, and Abdullah M. Assiri. Expression profiling of wd40 family genes including ddb1- and cul4- associated factor (dcaf) genes in mice and human suggests important regulatory roles in testicular development and spermatogenesis. BMC Genomics, Aug 2020. URL: https://doi.org/10.1186/s12864-020-07016-9, doi:10.1186/s12864-020-07016-9. This article has 32 citations and is from a peer-reviewed journal.
(mistry2020expressionprofilingof pages 2-4): Bhavesh V. Mistry, Maha Alanazi, Hanae Fitwi, Olfat Al-Harazi, Mohamed Rajab, Abdullah Altorbag, Falah Almohanna, Dilek Colak, and Abdullah M. Assiri. Expression profiling of wd40 family genes including ddb1- and cul4- associated factor (dcaf) genes in mice and human suggests important regulatory roles in testicular development and spermatogenesis. BMC Genomics, Aug 2020. URL: https://doi.org/10.1186/s12864-020-07016-9, doi:10.1186/s12864-020-07016-9. This article has 32 citations and is from a peer-reviewed journal.