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UBL7

Ubiquitin-like protein 7 · UniProt Q96S82

Length
380 aa
Mass
40.5 kDa
Annotated
2026-06-10
14 papers in source corpus 4 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBL7 is a ubiquilin-family ubiquitin-like protein that functions as a ubiquitin-binding adaptor coupling substrate recognition to two distinct cellular outcomes: protein quality control and antiviral signaling (PMID:16731964, PMID:36943869, PMID:40268954). Its C-terminal UBA domain forms a three-helix bundle that directly engages the conserved hydrophobic surface of ubiquitin (Leu8, Ile44, Val70) through residues Met76, Ile78, and Leu99 with a dissociation constant of ~17 µM, providing the molecular basis for its adaptor activity (PMID:16731964). In protein homeostasis, UBL7 associates with the VCP complex and the proteasome and shuttles substrates between them, slowing the proteasomal degradation of ERAD substrates; this activity is essential for spermiogenesis, where it protects spermatid factors including IFT140, SPATA20, and HK1/SLC2a3, and its loss in knockout mice causes severe sperm head and tail malformations (PMID:40268954). In innate immunity, UBL7 interacts with the E3 ligase TRIM21 and promotes TRIM21–MAVS association to drive K27-linked polyubiquitination of MAVS and TBK1 recruitment, amplifying type I interferon signaling, with UBL7-deficient mice showing increased viral susceptibility (PMID:36943869).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2003 Low

    Establishing UBL7 as a ubiquilin-related protein with a defined UBQ-UBA domain architecture framed it as a candidate ubiquitin-system adaptor rather than an orphan ORF.

    Evidence cDNA cloning, sequence/domain analysis, and stimulus-dependent expression profiling in BMSC and HL60 cells

    PMID:12644319

    Open questions at the time
    • No direct functional or binding experiment beyond cloning and sequence homology
    • Expression changes not linked to any mechanism
    • Domain function inferred from homology, not tested
  2. 2006 High

    Resolving how the UBA domain recognizes ubiquitin answered whether UBL7 can physically read the ubiquitin signal, defining the structural and energetic basis of its adaptor activity.

    Evidence Solution NMR structure, chemical shift perturbation mapping, mutagenesis, and HADDOCK complex modeling with KD measurement

    PMID:16731964

    Open questions at the time
    • Binding measured for mono-ubiquitin; chain-linkage preference of the UBA domain not determined
    • Does not connect ubiquitin binding to a cellular substrate or pathway
    • Role of the N-terminal UBQ domain not addressed
  3. 2023 High

    Identifying UBL7 as a TRIM21 partner that promotes MAVS K27-ubiquitination placed it within antiviral IFN signaling, showing it is not a generic degradation factor but a signaling amplifier.

    Evidence Reciprocal Co-IP, dose-dependent interaction assays, polyubiquitination assays, ISG induction, and viral-infection phenotype in knockout mice

    PMID:36943869

    Open questions at the time
    • Whether the UBA domain's ubiquitin binding is required for the TRIM21–MAVS function not dissected
    • Mechanism by which UBL7 bridges TRIM21 to MAVS not structurally defined
    • Relationship between this signaling role and proteasomal functions unresolved
  4. 2025 High

    Demonstrating that UBL7 shuttles substrates between VCP and the proteasome to slow their degradation defined its role in protein quality control and explained its essentiality for spermiogenesis.

    Evidence Knockout mouse phenotyping, Co-IP with VCP and proteasome, two-step IP-MS substrate identification, and protein degradation rate assays

    PMID:40268954

    Open questions at the time
    • Mechanism of substrate selection (IFT140, SPATA20, HK1/SLC2a3) not defined
    • How shuttling slows rather than promotes degradation mechanistically unclear
    • Connection to the UBA ubiquitin-binding interface not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ubiquitin-binding adaptor coordinates two seemingly opposing roles—protecting substrates from proteasomal degradation versus driving K27-ubiquitination in antiviral signaling—remains unresolved.
  • No unifying model linking the UBA/UBQ domains to both VCP-proteasome shuttling and TRIM21-MAVS signaling
  • Tissue- or context-specific partner switching not characterized
  • Structural basis of complex assembly with VCP, proteasome, or TRIM21 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Pathway
R-HSA-168256 Immune System 1 R-HSA-392499 Metabolism of proteins 1
Partners
HK1IFT140MAVSSPATA20TBK1TRIM21VCP

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 The UBA domain of human BMSC-UbP (UBL7) adopts a three-helix bundle with a hydrophobic patch (M-G-I motif in helix-1, loop-1, helix-3) that binds the conserved hydrophobic surface of ubiquitin (Leu8, Ile44, His68, Val70) via residues Met76, Ile78, and Leu99, with a dissociation constant of ~17 µM. Solution NMR structure determination, chemical shift perturbation mapping, mutagenesis, and HADDOCK-based complex modeling Protein Science High 16731964
2003 BMSC-UbP (UBL7) is a ubiquitin-like protein encoded by a 380-amino-acid ORF containing an N-terminal ubiquitin domain (UBQ) and a C-terminal ubiquitin-associated (UBA) domain, sharing homology with ubiquilin family members; its mRNA expression is modulated in a cell-type- and stimulus-specific manner (decreased in BMSC with PMA, increased in HL60 with LPS). cDNA library screening, sequence analysis, Northern blot/RT-PCR expression profiling Immunology Letters Low 12644319
2023 UBL7 enhances antiviral innate immunity by interacting with the E3 ubiquitin ligase TRIM21 and promoting TRIM21–MAVS association in a dose-dependent manner, thereby facilitating K27-linked polyubiquitination of MAVS and recruitment of TBK1 to potentiate IFN signaling. UBL7-deficient mice show increased viral susceptibility with attenuated antiviral immunity. Co-immunoprecipitation, knockout mouse model (viral infection phenotype), polyubiquitination assays, dose-dependent interaction assays, ISG induction analysis Cell Reports High 36943869
2025 UBL7 is required for spermiogenesis; it interacts with the VCP complex and proteasomes, shuttles substrates between them, and slows proteasomal degradation of ERAD substrates. Key protected spermatid factors identified by two-step immunoprecipitation include IFT140 (manchette), SPATA20 (head-tail coupling apparatus), and HK1/SLC2a3 (cytoplasmic droplets). UBL7 knockout mice display severe sperm head and tail malformations. Knockout mouse model, co-immunoprecipitation with VCP complex and proteasomes, two-step immunoprecipitation mass spectrometry substrate identification, protein degradation rate assays Nature Communications High 40268954

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Autoantibody signature in hepatocellular carcinoma using seromics. Journal of hematology & oncology 48 32616055
2006 Solution structure of the ubiquitin-associated domain of human BMSC-UbP and its complex with ubiquitin. Protein science : a publication of the Protein Society 48 16731964
2021 HYPK coordinates degradation of polyneddylated proteins by autophagy. Autophagy 21 34836490
2023 UBL7 enhances antiviral innate immunity by promoting Lys27-linked polyubiquitination of MAVS. Cell reports 15 36943869
2003 Cloning and identification of a novel ubiquitin-like protein, BMSC-UbP, from human bone marrow stromal cells. Immunology letters 15 12644319
2015 t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders. Molecular cancer 14 26671595
2016 GNB2 is a mediator of lidocaine-induced apoptosis in rat pheochromocytoma PC12 cells. Neurotoxicology 11 27018092
2022 Therapy-resistant and -sensitive lncRNAs, SNHG1 and UBL7-AS1 promote glioblastoma cell proliferation. Oxidative medicine and cellular longevity 8 35313638
2025 Inferring past demography and genetic adaptation in Spain using the GCAT cohort. Scientific reports 4 40274920
2025 UBL7 is indispensable for spermiogenesis through protecting critical factors from excessive degradation by proteasomes. Nature communications 2 40268954
2022 Tetramethylpyrazine Inhibits the Proliferation and Invasion of Glioma Cells by Regulating the UBL7-AS1/miR-144-3p Pathway. Evidence-based complementary and alternative medicine : eCAM 2 36045665
2026 Sex-specific autosomal susceptibility loci in systemic sclerosis: a genome-wide association study. The Lancet. Rheumatology 1 41999721
2024 An autoantibody profile identified by human genome-wide protein arrays in rheumatoid arthritis. MedComm 0 39132510
2023 Retracted: Tetramethylpyrazine Inhibits the Proliferation and Invasion of Glioma Cells by Regulating the UBL7-AS1/miR-144-3p Pathway. Evidence-based complementary and alternative medicine : eCAM 0 38125096

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