UFD-1 (Ubiquitin Fusion Degradation protein 1) is an essential cofactor of the CDC-48/p97 AAA ATPase segregase complex in C. elegans. Together with NPL-4, UFD-1 forms a heterodimeric cofactor that directs CDC-48 activity toward polyubiquitinated substrates. The CDC-48/UFD-1/NPL-4 complex plays critical roles in two major cellular processes: (1) ER-associated degradation (ERAD), where it extracts misfolded ubiquitinated proteins from the ER membrane for proteasomal degradation, and (2) DNA replication regulation, where it coordinates the degradation of replication licensing factors and the disassembly of replisome components. UFD-1 is essential for embryonic development, with RNAi knockdown causing embryonic lethality due to S-phase progression defects and activation of the DNA replication checkpoint. In adults, UFD-1 depletion causes germline developmental defects and accumulation of misfolded proteins in the ER.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: UFD-1 functions as part of the CDC-48/UFD-1/NPL-4 complex in ER-associated protein degradation (ERAD). This annotation is strongly supported by direct experimental evidence in C. elegans showing that ufd-1 RNAi induces ER stress and causes accumulation of misfolded proteins (PMID:16647269). The IBA annotation is consistent with the conserved function across eukaryotes. Reason: This is a core function of UFD-1. The CDC-48/UFD-1/NPL-4 complex is required for the cytoplasmic elimination of misfolded proteins exported from the ER, preventing activation of the unfolded protein response. Direct experimental evidence in C. elegans confirms this conserved role. Supporting Evidence: PMID:16647269 In Caenorhabditis elegans two homologs of p97, designated CDC-48.1 and CDC-48.2, exist. Our results indicate that both p97 homologs interact with UFD-1/NPL-4 in a similar CDC-48(UFD-1/NPL-4) complex. RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen. file:worm/ufd-1/ufd-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0031593 polyubiquitin modification-dependent protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: UFD-1 contains domains that recognize ubiquitinated substrates as part of the CDC-48 segregase complex. This molecular function is conserved across eukaryotes and enables substrate recruitment to the CDC-48 machinery for extraction and degradation. Reason: This is a core molecular function of UFD-1. The ability to bind polyubiquitinated proteins is essential for UFD-1's role in directing CDC-48 to its substrates in both ERAD and chromatin-associated degradation pathways. The IBA annotation reflects the conserved biochemical function of the UFD1 family. Supporting Evidence: PMID:16647269 It has been reported that the AAA ATPase p97/VCP/CDC48 is required in this pathway for protein dislocation across the ER membrane and subsequent ubiquitin dependent degradation by the 26S proteasome in the cytosol. Throughout ER-associated protein degradation, p97 cooperates with a binary Ufd1/Npl4-complex. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IBA GO_REF:0000033 | ACCEPT | Summary: UFD-1 is a core component of the CDC-48/NPL-4/UFD-1 complex (the C. elegans equivalent of the mammalian VCP-NPL4-UFD1 complex). This is extensively documented with direct experimental evidence showing physical interaction between UFD-1, CDC-48.1, CDC-48.2, and NPL-4 in C. elegans. Reason: This is a fundamental aspect of UFD-1 function. Multiple studies demonstrate that UFD-1 forms a stable complex with CDC-48 and NPL-4 in C. elegans, with co-immunoprecipitation and functional studies confirming this complex. Supporting Evidence: PMID:16647269 Our results indicate that both p97 homologs interact with UFD-1/NPL-4 in a similar CDC-48(UFD-1/NPL-4) complex. PMID:20977550 All six UBXN proteins directly interacted with CDC-48.1 and CDC-48.2 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UFD-1 localizes to both nucleus and cytoplasm in a cell-cycle dependent manner. Nuclear localization is supported by experimental evidence showing UFD-1 is present in purified nuclei and functions in chromatin-associated degradation during DNA replication. Reason: The IEA annotation based on UniProt subcellular location is consistent with direct experimental evidence. UFD-1 enters the nucleus upon nuclear membrane re-assembly in a CDC-48-dependent manner and functions there during S phase. Supporting Evidence: PMID:18728180 Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UFD-1 localizes to the cytoplasm during mitosis, where it also functions in ERAD by extracting misfolded proteins from the ER for proteasomal degradation. Reason: The IEA annotation is consistent with the known functions of UFD-1 in ERAD, which occurs in the cytoplasm. UFD-1 shows dynamic localization between cytoplasm and nucleus depending on cell cycle stage. Supporting Evidence: PMID:16647269 Protein degradation mediated by the ubiquitin/proteasome system is essential for the elimination of misfolded proteins from the endoplasmic reticulum (ER) to adapt to ER stress. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: UFD-1 functions in the ubiquitin fusion degradation pathway, facilitating the targeting of ubiquitinated substrates for proteasomal degradation. This is consistent with the InterPro domain annotation and the well-characterized function of UFD1 family proteins. Reason: This annotation accurately reflects UFD-1's role in promoting proteasomal degradation of ubiquitinated substrates. The CDC-48/UFD-1/NPL-4 complex extracts ubiquitinated proteins and delivers them to the proteasome. Supporting Evidence: PMID:16647269 It has been reported that the AAA ATPase p97/VCP/CDC48 is required in this pathway for protein dislocation across the ER membrane and subsequent ubiquitin dependent degradation by the 26S proteasome in the cytosol. |
| GO:0010498 proteasomal protein catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: UFD-1 promotes proteasomal degradation as part of the CDC-48 complex, which extracts ubiquitinated substrates and delivers them to the 26S proteasome. Reason: This annotation is consistent with the known function of the CDC-48/UFD-1/NPL-4 complex in promoting proteasomal degradation of extracted substrates. The ARBA machine learning inference is supported by experimental evidence. Supporting Evidence: PMID:16647269 subsequent ubiquitin dependent degradation by the 26S proteasome in the cytosol |
| GO:0005515 protein binding | IPI PMID:11731503 Identification of potential interaction networks using seque... | MODIFY | Summary: This annotation is based on interolog prediction from conserved protein-protein interactions. The interaction partner is NPL-4.2 (Q95QZ9). While the interaction is valid, the term 'protein binding' is too general and should be replaced with more informative terms. Reason: The generic 'protein binding' annotation should be replaced with more specific terms that describe the functional nature of the interaction. UFD-1 interacts with NPL-4 as part of a functional heterodimeric cofactor for CDC-48, which is better captured by the VCP-NPL4-UFD1 complex annotation. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex Supporting Evidence: PMID:11731503 Identification of potential interaction networks using sequence-based searches for conserved protein-protein interactions or "interologs". |
| GO:0005515 protein binding | IPI PMID:14704431 A map of the interactome network of the metazoan C. elegans. | MODIFY | Summary: This annotation derives from the C. elegans interactome mapping project. The interaction with NPL-4.2 was identified through yeast two-hybrid screening. While valid, 'protein binding' is too general. Reason: The Y2H-based interaction data should be annotated with more specific terms. The UFD-1/NPL-4 interaction forms a functional heterodimer that serves as the CDC-48 cofactor. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex Supporting Evidence: PMID:14704431 Jan 2. A map of the interactome network of the metazoan C. |
| GO:0005515 protein binding | IPI PMID:20977550 Caenorhabditis elegans UBX cofactors for CDC-48/p97 control ... | MODIFY | Summary: This annotation documents UFD-1 interactions with CDC-48.1 (P54811) and UBX domain-containing proteins (H2KYU6, H2L056). The study demonstrates that UBXN proteins, UFD-1, and NPL-4 can simultaneously associate with CDC-48 hexamers. Reason: The generic 'protein binding' should be replaced with the more informative complex membership annotation, as these interactions occur in the context of the functional CDC-48 segregase complex. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex Supporting Evidence: PMID:20977550 Epub 2010 Oct 26. Caenorhabditis elegans UBX cofactors for CDC-48/p97 control spermatogenesis. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IDA PMID:20977550 Caenorhabditis elegans UBX cofactors for CDC-48/p97 control ... | ACCEPT | Summary: This annotation documents direct experimental evidence showing UFD-1 is part of a complex with CDC-48.1 and CDC-48.2 in C. elegans. The study demonstrated these proteins form stable complexes that regulate spermatogenesis. Reason: Direct experimental evidence from co-IP and functional studies confirms UFD-1 as a component of the CDC-48 complex in C. elegans. This is a core aspect of UFD-1 function. Supporting Evidence: PMID:20977550 All six UBXN proteins directly interacted with CDC-48.1 and CDC-48.2 |
| GO:0044877 protein-containing complex binding | IDA PMID:20977550 Caenorhabditis elegans UBX cofactors for CDC-48/p97 control ... | KEEP AS NON CORE | Summary: This annotation indicates UFD-1 can bind protein complexes. While technically accurate, this is a very general term. UFD-1 binds to the CDC-48 hexamer and may also interact with substrate complexes during extraction. Reason: While not incorrect, this is a very general annotation. The more specific complex membership (VCP-NPL4-UFD1 AAA ATPase complex) better captures the functional relevance. This annotation can be retained as non-core. Supporting Evidence: PMID:20977550 Epub 2010 Oct 26. Caenorhabditis elegans UBX cofactors for CDC-48/p97 control spermatogenesis. |
| GO:1900182 positive regulation of protein localization to nucleus | IMP PMID:26842564 Chromatin-associated degradation is defined by UBXN-3/FAF1 t... | ACCEPT | Summary: PMID:26842564 demonstrates that proper nuclear localization of UBXN-3 during S phase depends on a functional CDC-48/UFD-1/NPL-4 complex. RNAi depletion of CDC-48 or UFD-1/NPL-4 results in formation of UBXN-3-positive punctae in the nucleoplasm rather than normal diffuse nuclear localization. Thus, UFD-1 positively regulates UBXN-3 nuclear localization. Reason: This annotation accurately reflects a specific regulatory function of UFD-1 documented in the cited publication. The CDC-48/UFD-1/NPL-4 complex is required for proper UBXN-3 nuclear localization during S phase, which is important for chromatin-associated degradation. Supporting Evidence: PMID:26842564 Indeed, RNAi-mediated depletion of CDC-48 or the cofactor UFD-1/NPL-4 resulted in the formation of UBXN-3-positive punctae in the nucleoplasm of worm embryos |
| GO:0005634 nucleus | IDA PMID:18723220 Measuring and modelling mixture toxicity of imidacloprid and... | ACCEPT | Summary: IMPORTANT: This annotation appears to cite the wrong publication. PMID:18723220 is a study about pesticide toxicity in C. elegans and earthworms, not about ufd-1 localization. The correct reference for ufd-1 nuclear localization is likely PMID:18728180, which demonstrates UFD-1 nuclear localization during cell cycle progression. Reason: The nuclear localization of UFD-1 is well-supported by PMID:18728180, which shows that the CDC-48(UFD-1/NPL-4) complex functions in S phase progression and is essential for embryonic cell division. The IEA annotation for nucleus (GO:0005634) also supports this localization. The cited PMID:18723220 appears to be a curation error but the annotation itself is valid. Supporting Evidence: PMID:18728180 Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. PMID:18723220 Measuring and modelling mixture toxicity of imidacloprid and thiacloprid on Caenorhabditis elegans and Eisenia fetida. |
| GO:0009792 embryo development ending in birth or egg hatching | IMP PMID:16647269 A conserved role of Caenorhabditis elegans CDC-48 in ER-asso... | KEEP AS NON CORE | Summary: RNAi-mediated knockdown of ufd-1 causes embryonic lethality in C. elegans, demonstrating that UFD-1 is required for embryonic development. However, this is a phenotypic annotation rather than describing a specific molecular function in development. Reason: While UFD-1 is essential for embryonic development, this represents a phenotypic consequence of UFD-1 loss rather than a specific developmental function. The lethality results from failure of core cellular processes (ERAD, DNA replication) rather than a developmental regulatory role. This should be kept as a non-core annotation. Supporting Evidence: PMID:16647269 RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen. PMID:18728180 Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IPI PMID:16647269 A conserved role of Caenorhabditis elegans CDC-48 in ER-asso... | ACCEPT | Summary: This annotation documents the physical interaction between UFD-1 and NPL-4 (interacting with WBGene00007352/npl-4.1) as part of the CDC-48 cofactor complex. The study demonstrated co-immunoprecipitation of these proteins in C. elegans. Reason: Direct experimental evidence demonstrates UFD-1 forms a complex with NPL-4 and CDC-48 in C. elegans. This is a core aspect of UFD-1 function. Supporting Evidence: PMID:16647269 Our results indicate that both p97 homologs interact with UFD-1/NPL-4 in a similar CDC-48(UFD-1/NPL-4) complex. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IPI PMID:16647269 A conserved role of Caenorhabditis elegans CDC-48 in ER-asso... | ACCEPT | Summary: This is a duplicate annotation documenting interaction with WBGene00008053 (cdc-48.1 or cdc-48.2). The study showed UFD-1 interacts with both CDC-48.1 and CDC-48.2 as part of the segregase complex. Reason: The interaction between UFD-1 and CDC-48 is well documented. Having multiple evidence lines for the same annotation (different interaction partners) is appropriate. Supporting Evidence: PMID:16647269 In Caenorhabditis elegans two homologs of p97, designated CDC-48.1 and CDC-48.2, exist. Our results indicate that both p97 homologs interact with UFD-1/NPL-4 |
| GO:0036503 ERAD pathway | IMP PMID:16647269 A conserved role of Caenorhabditis elegans CDC-48 in ER-asso... | ACCEPT | Summary: Direct experimental evidence from RNAi studies demonstrates UFD-1 is required for ERAD in C. elegans. Depletion of ufd-1 induces ER stress and causes accumulation of misfolded proteins in the ER lumen. Reason: This is a core function of UFD-1 with strong experimental support. The CDC-48/UFD-1/NPL-4 complex is essential for extracting misfolded proteins from the ER for degradation. Supporting Evidence: PMID:16647269 RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen. Together, these data suggest an evolutionarily conserved retro-translocation machinery at the endoplasmic reticulum. |
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Download this section (compressed HTML)Q: Does C. elegans UFD-1 have specific roles in chromatin-associated degradation beyond UBXN-3/CDT-1 regulation? While studies have focused on UBXN-3-dependent functions, the mammalian VCP/p97 complex has many chromatin substrates. Systematic identification of UFD-1-dependent chromatin substrates in C. elegans would be valuable.
Q: Are there tissue-specific functions of UFD-1 beyond germline and embryonic development? Most studies focus on early development. Understanding UFD-1 function in differentiated adult tissues could reveal additional roles.
Experiment: Proximity labeling (BioID or TurboID) to identify UFD-1-proximal proteins in different subcellular compartments and cell cycle stages. This would provide a comprehensive view of UFD-1 interaction partners and potential substrates beyond those currently characterized.
Experiment: Structure-function analysis of UFD-1 domains to determine requirements for ERAD vs. chromatin-associated degradation functions. Understanding whether these functions are separable could provide insights into pathway-specific regulation.
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