Affinage

ATRNL1

Attractin-like protein 1 · UniProt Q5VV63

Length
1379 aa
Mass
152.6 kDa
Annotated
2026-06-09
22 papers in source corpus 7 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATRNL1 is a transmembrane adapter that controls melanocortin receptor abundance and participates in pigmentation and cardiac physiology (PMID:18064672, PMID:41178558, PMID:40196599). It recruits the RING-domain E3 ubiquitin ligase MGRN1 to promote ubiquitylation and surface/ciliary degradation of the melanocortin receptors MC1R and MC4R, such that loss of the ATRNL1/MGRN1 axis increases receptor levels and enhances eumelanin production in melanocytes (PMID:41178558, PMID:40196599). ATRNL1 is functionally redundant with its paralog ATRN from a gain-of-function standpoint: transgenic overexpression rescues agouti pigmentation and delays spongiform neurodegeneration in Atrn-null mice, although Atrnl1 knockout alone produces no overt pigmentation, CNS, or body-weight phenotype, placing the two genes in a shared pathway (PMID:18064672, PMID:18821597). Beyond pigmentation, ATRNL1 localizes to cardiomyocyte intercalated disks and modulates the cardiac action potential and stress response, and is overexpressed in atrial fibrillation (PMID:39562555). Its transcription is directly activated by CEBPB binding its promoter, and in cervical cancer cells ATRNL1 suppresses cell viability, migration, and epithelial-mesenchymal transition (PMID:38158696).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2007 High

    Established whether ATRNL1 and its paralog ATRN are functionally interchangeable, resolving that ATRNL1 can substitute for ATRN when overexpressed but is dispensable on its own.

    Evidence Atrnl1 knockout and beta-actin-driven Atrnl1 transgene in Atrn-null mice, scored for pigmentation, CNS pathology, and body weight

    PMID:18064672

    Open questions at the time
    • Did not define the molecular basis of redundancy or the endogenous role masked by paralog compensation
    • No biochemical mechanism linking ATRNL1 to pigmentation identified at this stage
  2. 2008 Medium

    Positioned ATRNL1/ATRN within the pigmentation genetic hierarchy and distinguished this pathway from the dal locus, refining pathway placement relative to Mc1r and agouti.

    Evidence Genetic epistasis crosses among dal, Atrn, Mc1r, and agouti mutants plus Atrnl1 transgenic rescue

    PMID:18821597

    Open questions at the time
    • Identity of the dal gene unknown, leaving the molecular relationship unresolved
    • No biochemical readout connecting ATRNL1 to melanocortin signaling
  3. 2023 Medium

    Identified an upstream transcriptional regulator of ATRNL1 and a tumor-suppressive function, showing CEBPB drives ATRNL1 expression to restrain cervical cancer cell behavior.

    Evidence ChIP and luciferase reporter for CEBPB promoter binding plus gain-of-function and rescue assays in cervical cancer cells

    PMID:38158696

    Open questions at the time
    • Mechanism by which ATRNL1 suppresses EMT and migration not defined
    • Single lab; not linked to the melanocortin/MGRN1 axis
  4. 2024 Medium

    Extended ATRNL1 function beyond pigmentation to the heart, localizing it to intercalated disks and tying it to action potential modulation and the cardiac stress response.

    Evidence snRNA-seq of >175,000 human left atrial nuclei plus subcellular localization and knockdown/overexpression functional assays in cardiomyocytes

    PMID:39562555

    Open questions at the time
    • Molecular partners mediating cardiac effects not identified
    • Whether the MGRN1/melanocortin adapter activity underlies cardiac function untested
  5. 2025 High

    Defined the biochemical mechanism: ATRNL1 acts as a transmembrane adapter recruiting the E3 ligase MGRN1 to ubiquitylate and degrade melanocortin receptors, unifying earlier pigmentation genetics with a molecular pathway.

    Evidence Reciprocal Co-IP mapping interaction to the MGRN1 RING domain, ubiquitylation and receptor degradation assays, surface/ciliary localization assays, and melanocyte eumelanin assays

    PMID:40196599 PMID:41178558

    Open questions at the time
    • Structural basis of ATRNL1-MGRN1 and ATRNL1-receptor recognition not determined
    • Whether this adapter activity operates in cardiomyocytes or cancer cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single transmembrane adapter integrates melanocortin receptor turnover, cardiac electrophysiology, and EMT suppression across tissues remains unresolved.
  • No mechanism connecting the MGRN1/receptor adapter role to cardiac or cancer phenotypes
  • Endogenous loss-of-function phenotype in human tissues uncharacterized
  • No structural model of the ATRNL1-MGRN1 complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-392499 Metabolism of proteins 1
Partners
ATRNCEBPBMC1RMC4RMGRN1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 ATRNL1 and ATRN are redundant from a gain-of-function but not loss-of-function perspective: transgenic overexpression of ATRNL1 in Atrn null mice rescued normal agouti-banded fur pigmentation and significantly delayed onset of spongiform neurodegeneration, demonstrating that ATRNL1 can compensate for ATRN loss. However, Atrnl1 knockout mice alone showed no pigmentation, CNS, or body weight phenotype. Loss-of-function and gain-of-function mouse genetics (Atrnl1 knockout mice, beta-actin promoter-driven Atrnl1 transgene in Atrn null background); phenotypic analysis of fur color, CNS pathology, body weight Genesis (New York, N.Y. : 2000) High 18064672
2008 Transgenic overexpression of ATRNL1 did not rescue dark-like (dal) mutant phenotypes (dark fur, testicular vacuolation, spongiform neurodegeneration), and dal and Atrn showed additive effects on these phenotypes. Genetic crosses placed dal upstream of Mc1r and downstream of agouti. This places ATRNL1 and ATRN in the same pathway, but ATRNL1 overexpression cannot compensate for the dal locus, distinguishing dal from the ATRN pathway. Genetic epistasis by crosses between dal, Atrn, Mc1r, and agouti mutant mice; Atrnl1 transgenic rescue experiment Genesis (New York, N.Y. : 2000) Medium 18821597
2025 ATRNL1 acts as a transmembrane adapter that recruits the E3 ubiquitin ligase MGRN1 (via its RING domain) to promote ubiquitylation and degradation of the melanocortin receptors MC1R and MC4R at the cell surface. Loss of MGRN1 or ATRN leads to increased surface and ciliary localization of MC4R in fibroblasts and elevated MC1R levels in melanocytes, resulting in enhanced eumelanin production. Co-immunoprecipitation (showing ATRNL1/ATRN interaction with MGRN1 RING domain); functional ubiquitylation and receptor degradation assays; cell surface/ciliary localization assays; melanocyte eumelanin production assay; loss-of-function experiments Journal of cell science High 40196599 41178558
2024 ATRNL1 is overexpressed in cardiomyocytes of patients with atrial fibrillation and localizes to intercalated disks. Both knockdown and overexpression of ATRNL1 in cardiomyocytes identified a role in the cell stress response and modulation of the cardiac action potential. Single-nucleus RNA-seq (snRNA-seq) on >175,000 nuclei from human left atrial samples; subcellular localization experiments; knockdown and overexpression functional experiments with action potential and stress response readouts Nature communications Medium 39562555
2023 CEBPB (CCAAT enhancer binding protein beta) transcriptionally upregulates ATRNL1 by binding to its promoter in cervical cancer cells. ATRNL1 upregulation suppresses cervical cancer cell viability, migration, and epithelial-mesenchymal transition (EMT), and the effects of CEBPB elevation on these processes are reversed by ATRNL1 depletion. ChIP assay (CEBPB binding to ATRNL1 promoter); luciferase reporter assay; gain-of-function and rescue experiments; RT-qPCR and western blotting Cellular and molecular biology (Noisy-le-Grand, France) Medium 38158696
2024 ATRNL1 and WNT9A are upregulated in both HCM cell models (isoproterenol-treated) and animal models, validating them as differentially expressed genes in hypertrophic cardiomyopathy. Propylthiouracil treatment significantly inhibited ATRNL1 expression in the HCM model. Isoproterenol-induced HCM cell and animal models; immunohistochemistry; bioinformatics integration; drug treatment experiments Frontiers in molecular biosciences Low 39329089

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Circular RNA CpG island hypermethylation-associated silencing in human cancer. Oncotarget 39 30018746
2021 Exploring the genetic architecture of feed efficiency traits in chickens. Scientific reports 33 33633287
2007 Genetic analysis of attractin homologs. Genesis (New York, N.Y. : 2000) 17 18064672
2021 Regulating effect of Circ_ATRNL1 on the promotion of SOX9 expression to promote chondrogenic differentiation of hAMSCs mediated by MiR-145-5p. Journal of tissue engineering and regenerative medicine 16 33734580
2010 De novo 325 kb microdeletion in chromosome band 10q25.3 including ATRNL1 in a boy with cognitive impairment, autism and dysmorphic features. European journal of medical genetics 15 20670697
2008 Genetic and phenotypic studies of the dark-like mutant mouse. Genesis (New York, N.Y. : 2000) 13 18821597
2024 Comprehensive single-cell analysis reveals heterogeneity of fibroblast subpopulations in ovarian cancer tissue microenvironment. Heliyon 12 38533040
2024 Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation. Nature communications 11 39562555
2022 Genomic Analysis of Gastrointestinal Parasite Resistance in Akkaraman Sheep. Genes 11 36553445
2020 Whole genome sequencing analysis of high confidence variants of B-cell lymphoma in Canis familiaris. PloS one 7 32857815
2015 Identification of atypical ATRNL1 insertion to EML4-ALK fusion gene in NSCLC. Lung cancer (Amsterdam, Netherlands) 7 25601488
2022 CircATRNL1 increases acid-sensing ion channel 1 to advance epithelial-mesenchymal transition in endometriosis by binding to microRNA-103a-3p. Reproductive biology 6 35504053
2025 The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters. Journal of cell science 5 41178558
2023 Transcriptional factor CCAAT enhancer binding protein beta inhibits epithelial-mesenchymal transition in cervical cancer via regulating attractin-like 1. Cellular and molecular biology (Noisy-le-Grand, France) 4 38158696
2025 The fusion characteristics of RET fusion in pan-cancer among the Chinese population: A comprehensive genomic analysis. Translational oncology 3 40184718
2025 The E3 ubiquitin ligase MGRN1 targets melanocortin receptors MC1R and MC4R via interactions with transmembrane adapters. bioRxiv : the preprint server for biology 3 40196599
2022 Modulation of autoimmune diabetes by N-ethyl-N-nitrosourea- induced mutations in non-obese diabetic mice. Disease models & mechanisms 3 35502705
2025 Genome-wide association and functional annotation analyses reveal candidate genes and pathways associated with various ewe longevity indicators in U.S. Katahdin sheep. Frontiers in genetics 2 40678382
2025 Embryonic temperature influences transcriptomic and methylation profiles in the liver of juvenile largemouth bass. Journal of thermal biology 1 40023986
2024 Identification of ATRNL1 and WNT9A as novel key genes and drug candidates in hypertrophic cardiomyopathy: integrative bioinformatics and experimental validation. Frontiers in molecular biosciences 1 39329089
2026 A predictive insight into the ATRNL1-mediated ceRNA network driving abdominal aortic aneurysm progression via VSMC phenotypic switching. Biochemical and biophysical research communications 0 42061003
2023 Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes. Pediatric diabetes 0 38590442

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