Affinage

TCAF1

TRPM8 channel-associated factor 1 · UniProt Q9Y4C2

Round 2 corrected
Length
921 aa
Mass
102.1 kDa
Annotated
2026-04-28
38 papers in source corpus 3 papers cited in narrative 3 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCAF1 is a TRP channel-associated regulatory protein that modulates the trafficking and activity of thermoTRP channels and protects genome stability under replication stress. TCAF1 binds TRPM8 and promotes its cell-surface trafficking in prostate epithelial cells, and the TCAF1–TRPM8 complex reduces prostate cancer cell migration speed and directionality, consistent with loss of TCAF1 expression in metastatic specimens (PMID:25559186). Under replication stress, TCAF1 facilitates dissociation of STING from TRPV2, relieving TRPV2 repression and enabling Ca²⁺ release that activates a CaMKK2/AMPK/Exo1 signaling axis required for stalled replication fork protection and chromosomal stability (PMID:38816425). TCAF1 and its paralog TCAF2 arose from segmental duplications ~1.7 million years ago and diversified exclusively in Homo sapiens, with copy number variation that may reflect adaptation to environmental pressures (PMID:34433829).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2015 High

    The identity of TRPM8-associated cofactors was unknown; discovery of TCAF1 as a direct TRPM8-binding partner that promotes channel surface trafficking and suppresses prostate cancer cell migration established it as a functionally important channel-regulatory protein.

    Evidence Reciprocal co-immunoprecipitation, surface trafficking assays, electrophysiological recordings, and migration assays in prostate cancer cells

    PMID:25559186

    Open questions at the time
    • Structural basis of the TCAF1–TRPM8 interaction is unresolved
    • Whether TCAF1 regulates TRPM8 in non-prostate tissues is untested
    • Mechanism by which TCAF1 opposes migration beyond channel gating effects is unclear
  2. 2021 Medium

    How TCAF1/TCAF2 paralogs arose and whether their copy number varies across human populations was unknown; long-read sequencing revealed that TCAF duplications originated ~1.7 Mya and diversified only in Homo sapiens, with population-level copy number variation linked to differential TCAF2/TRPM8 expression.

    Evidence Long-read sequencing of complex segmental duplications, primate comparative genomics, population genetic selection analysis

    PMID:34433829

    Open questions at the time
    • Functional consequences of TCAF1 copy number variation on protein activity are not experimentally tested
    • Whether copy number variation in TCAF1 specifically (vs TCAF2) affects channel regulation is unresolved
    • Selective pressures driving TCAF diversification remain correlative
  3. 2024 High

    Whether TCAF1 functions beyond TRP channel trafficking was unknown; a genome-wide CRISPR screen revealed that TCAF1 promotes TRPV2-mediated Ca²⁺ release under replication stress by facilitating STING dissociation from TRPV2, activating a CaMKK2/AMPK/Exo1 pathway that protects stalled forks and maintains chromosomal stability.

    Evidence Genome-wide CRISPR screen, Ca²⁺ imaging, co-immunoprecipitation of STING–TRPV2, epistasis analysis of CaMKK2/AMPK/Exo1, chromosomal stability and cell survival assays

    PMID:38816425

    Open questions at the time
    • Whether TCAF1 directly binds TRPV2 or acts indirectly through STING displacement is not resolved
    • Relative importance of TCAF1's TRPM8-regulatory versus TRPV2/replication-stress functions in vivo is unknown
    • Whether TCAF1-mediated fork protection operates in non-cancer cell contexts is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of TCAF1 interactions with TRP channels, whether TCAF1's TRPM8-trafficking and TRPV2/replication-stress functions are coordinated or context-dependent, and the in vivo physiological consequence of TCAF1 loss.
  • No structural data exist for TCAF1 or any TCAF1–channel complex
  • No animal knockout or disease model has been reported
  • Whether TCAF1 regulates additional TRP family members beyond TRPM8 and TRPV2 is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-73894 DNA Repair 1
Partners
STINGTRPM8TRPV2

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 TCAF1 and TCAF2 are novel TRPM8-binding partner proteins ('TRP channel-associated factors'). Both bind to the TRPM8 channel and promote its trafficking to the cell surface, but exert opposing effects on TRPM8 gating: TCAF1/TRPM8 interaction reduces the speed and directionality of migration of prostate cancer cells, consistent with loss of TCAF1 expression in metastatic specimens, while TCAF2 promotes migration. Co-immunoprecipitation, cell surface trafficking assays, functional channel gating recordings, migration assays, and loss-of-function experiments in prostate cancer cells The Journal of cell biology High 25559186
2024 TCAF1 is a key factor promoting TRPV2-mediated Ca2+ release under replication stress. Mechanistically, TCAF1 facilitates dissociation of STING from TRPV2, thereby relieving TRPV2 repression; this Ca2+ release activates CaMKK2/AMPK, leading to Exo1 phosphorylation that prevents aberrant fork processing. TCAF1 is required for fork protection, chromosomal stability, and cell survival after replication stress. Genome-wide CRISPR-based screen, Ca2+ release assays, co-immunoprecipitation (STING–TRPV2 interaction), epistasis analysis (CaMKK2/AMPK/Exo1 pathway), chromosomal stability assays, and cell survival assays after replication stress Nature communications High 38816425
2021 TCAF1/TCAF2 copy number variation is substantial in humans, with TCAF duplications originating ~1.7 million years ago and diversifying only in Homo sapiens. TCAF2 expression differs between haplogroups, with high TCAF2 and TRPM8 expression in liver and prostate, supporting a role for TCAF diversification in cold or dietary adaptation. Long-read sequencing to resolve complex segmental duplications, copy number variant analysis across primate genomes, full-length transcript annotation, population genetic selection analysis Nature communications Medium 34433829

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2011 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 286 21903422
2018 K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains. Proceedings of the National Academy of Sciences of the United States of America 227 29378950
2004 Lineage-specific gene duplication and loss in human and great ape evolution. PLoS biology 224 15252450
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2005 Large-scale analysis of the human ubiquitin-related proteome. Proteomics 154 16196087
2017 An Interaction Landscape of Ubiquitin Signaling. Molecular cell 119 28190767
2017 The evolution and population diversity of human-specific segmental duplications. Nature ecology & evolution 112 28580430
2021 Sequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation. Nature communications 103 34504087
1998 Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 103 9872452
2017 R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. Nature communications 94 28561026
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2015 TRP channel-associated factors are a novel protein family that regulates TRPM8 trafficking and activity. The Journal of cell biology 83 25559186
2019 The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification. The EMBO journal 82 31403225
2017 Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones. The Journal of cell biology 78 28515276
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2021 Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy. Acta pharmaceutica Sinica. B 66 35256949
2020 Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells. PLoS biology 65 32687490
2017 RHCG and TCAF1 promoter hypermethylation predicts biochemical recurrence in prostate cancer patients treated by radical prostatectomy. Oncotarget 28 28052017
2021 Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans. Nature communications 17 34433829
2023 Liver transcriptome profiles of dairy cows with different serum metabotypes. Journal of dairy science 9 37806621
2022 The Association between TRP Channels Expression and Clinicopathological Characteristics of Patients with Pancreatic Adenocarcinoma. International journal of molecular sciences 9 36012311
2024 TCAF1 promotes TRPV2-mediated Ca2+ release in response to cytosolic DNA to protect stressed replication forks. Nature communications 8 38816425
2023 Application of serum peptidomics for Parkinson's disease in SNCA-A30P mice. Heliyon 2 38125428