Affinage

LRCH1

Leucine-rich repeat and calponin homology domain-containing protein 1 · UniProt Q9Y2L9

Length
728 aa
Mass
80.9 kDa
Annotated
2026-06-10
19 papers in source corpus 5 papers cited in narrative 5 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

LRCH1 is a cytoplasmic adaptor protein that acts as a negative regulator of immune cell migration and effector activation across multiple cell types (PMID:28028151, PMID:32727906). In T cells it restrains directional migration by sequestering the guanine-nucleotide exchange factor DOCK8 and competing with Cdc42, thereby limiting DOCK8 GEF activity; chemokine signaling through PKCα phosphorylates DOCK8 at three serine sites to release it from LRCH1 and permit its translocation to the leading edge, and Lrch1-deficient mice develop more severe EAE while Lrch1 transgenics are protected (PMID:28028151). LRCH1 also dampens lymphocyte activation by binding the transmembrane adapter LAT, reducing LAT phosphorylation and its association with GRB2 and promoting LAT endocytosis, which suppresses signalosome assembly and CD8+ T cell proliferation and cytotoxicity; its loss enhances anti-viral, anti-bacterial, and anti-tumor responses and improves human CAR T cell migration and proliferation (PMID:32727906). A parallel inhibitory role in NK cells operates through attenuation of Src and Lck kinase activation, limiting cytokine and granzyme B output and tumor cytotoxicity (PMID:32173150). Beyond lymphoid cells, LRCH1 restrains microglia-mediated neuroinflammation by limiting p38 MAPK and Erk1/2 activation and pro-inflammatory polarization (PMID:32631435). The structural basis of LRCH1's adaptor interactions has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2017 High

    Established LRCH1's first molecular mechanism: how a negative regulator could couple chemokine sensing to control of Rho-family GTPase-driven T cell migration.

    Evidence Two-hybrid screen, reciprocal co-IP, DOCK8 serine-site mutagenesis, and Lrch1 KO/transgenic mouse EAE models with migration assays

    PMID:28028151

    Open questions at the time
    • No structural model of the LRCH1–DOCK8 interface
    • Whether LRCH1 regulates GEFs other than DOCK8 not addressed
    • The PKCα substrate relationship within this module not directly resolved for LRCH1 itself
  2. 2020 High

    Identified a distinct LRCH1 mechanism in effector lymphocytes—direct control of the LAT signalosome—extending its role from migration to antigen-driven activation and cytotoxicity.

    Evidence Direct LRCH1–LAT co-IP, phosphorylation and endocytosis assays, Lrch1-/- infection and B16 tumor models, and LRCH1 KO in human CAR T cells

    PMID:32727906

    Open questions at the time
    • Mechanism by which LRCH1 promotes LAT endocytosis unresolved
    • Relationship between the LAT and DOCK8 functions of LRCH1 not integrated
    • No structural basis for LRCH1–LAT binding
  3. 2020 Medium

    Showed LRCH1's suppressive function generalizes to NK cells via attenuation of proximal Src/Lck kinase signaling rather than receptor expression.

    Evidence CRISPR-Cas9 LRCH1 KO in NK-92 and primary human NK cells with cytokine/granzyme B and Src/Lck activation readouts plus in vivo killing assays

    PMID:32173150

    Open questions at the time
    • Direct LRCH1 binding partner in NK cells not identified
    • Link between Src/Lck attenuation and any LAT- or DOCK8-dependent mechanism not established
    • Single-lab study
  4. 2020 Medium

    Placed LRCH1 upstream of PKCα in CD4+ T cell chemotaxis, reinforcing its selective control of migration without affecting differentiation.

    Evidence Lentiviral overexpression/knockdown in human CD4+ T cells with Transwell chemotaxis toward CXCL12 and differentiation/cytokine profiling

    PMID:32210709

    Open questions at the time
    • Molecular target linking LRCH1 to PKCα in CD4+ cells not defined
    • Whether the DOCK8 module operates in CD4+ cells not tested
    • Single-lab study
  5. 2020 Medium

    Extended LRCH1's anti-inflammatory function beyond lymphocytes to innate myeloid cells of the CNS.

    Evidence Lentiviral LRCH1 knockdown in primary microglia with cytokine, polarization, and MAPK phosphorylation readouts plus adoptive transfer into a rat SCI model

    PMID:32631435

    Open questions at the time
    • Direct molecular target of LRCH1 in microglia not identified
    • Mechanism linking LRCH1 to p38/Erk1/2 unresolved
    • Knockdown rather than clean knockout

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the migration (DOCK8), activation (LAT), kinase (Src/Lck), and MAPK functions of LRCH1 reflect one unifying biochemical activity or distinct context-specific adaptor roles remains unresolved.
  • No structural or domain-level mechanism unifying the partners
  • No biochemical activity assigned to the LRR/CH domains
  • Cross-talk among the partners untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
DOCK8LAT

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 LRCH1 competes with Cdc42 for binding to DOCK8, thereby restraining DOCK8's guanine-nucleotide exchange factor (GEF) activity toward Cdc42 and inhibiting T cell migration. In response to chemokine stimulation, PKCα phosphorylates DOCK8 at three serine sites, promoting DOCK8 dissociation from LRCH1 and translocation to the leading edge. Point mutations at the DOCK8 serine sites block chemokine- and PKCα-induced T cell migration. Lrch1-deficient mice display more severe experimental autoimmune encephalomyelitis (EAE), while Lrch1 transgenic mice are protected, establishing LRCH1 as a negative regulator of the PKCα–DOCK8–Cdc42 migration module. Two-hybrid screening, co-immunoprecipitation, point mutagenesis of DOCK8 serine sites, Lrch1 transgenic and knockout mouse EAE model, directional migration assays The Journal of experimental medicine High 28028151
2020 LRCH1 directly binds the transmembrane adapter protein LAT, reduces LAT phosphorylation, reduces LAT interaction with GRB2, and promotes LAT endocytosis, thereby dampening LAT signalosome formation and CD8+ T cell activation. Lrch1-knockout mice show enhanced CD8+ T cell proliferation and cytotoxicity against influenza virus, Listeria, and B16 tumor cells. Knockout of LRCH1 in human CAR T cells improved their migration and proliferation in vitro. Co-immunoprecipitation (direct LRCH1–LAT binding), phosphorylation assays, endocytosis assays, Lrch1-/- mouse infection and tumor models, adoptive transfer of Lrch1-/- CD8+ CTLs, LRCH1 KO in human CAR T cells Proceedings of the National Academy of Sciences of the United States of America High 32727906
2020 LRCH1 knockdown in microglia increased production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) after LPS/ATP priming, promoted polarization toward iNOS-expressing (pro-inflammatory) microglia, enhanced microglia-mediated N27 neuron death, and increased activation of p38 MAPK and Erk1/2 signaling. Adoptive injection of LRCH1-knockdown microglia into rat spinal cords worsened post-SCI inflammation, tissue damage, and locomotor function, establishing LRCH1 as a negative regulator of microglia-mediated neuroinflammation via p38 MAPK and Erk1/2 pathways. Lentivirus-mediated LRCH1 knockdown in primary microglia, cytokine ELISA/qPCR, flow cytometry for polarization markers, p38 MAPK and Erk1/2 phosphorylation assays, adoptive transfer into rat SCI model with behavioral and histological readouts Journal of neuroinflammation Medium 32631435
2020 LRCH1 inhibits NK-92 cell cytotoxicity against tumor cells. LRCH1 knockout (CRISPR-Cas9) did not affect basal NK-92 cell survival or natural cytotoxicity receptor expression, but upon tumor cell contact increased production of IFN-γ, TNF-α, IL-2, and granzyme B, and enhanced Src and Lck kinase activation. Primary human NK cells showed similar cytokine increases upon LRCH1 knockout, identifying Src/Lck signaling as the pathway negatively regulated by LRCH1 in NK cells. CRISPR-Cas9 knockout of LRCH1 in NK-92 cells and primary human NK cells, cytokine/granzyme B measurement, Src and Lck kinase activation assays, in vivo tumor killing assay Immunobiology Medium 32173150
2020 LRCH1 inhibits the migratory capacity of CD4+ T cells toward CXCL12. Lentiviral overexpression or knockdown of LRCH1 did not affect CD4+ T cell differentiation or related cytokine expression, but modulated chemotaxis in a PKCα-dependent manner, placing LRCH1 upstream of PKCα in CD4+ T cell migration. Lentiviral LRCH1 overexpression and knockdown in peripheral blood CD4+ T cells, Transwell chemotaxis assay toward CXCL12, flow cytometry for differentiation markers, cytokine ELISA/qPCR International journal of medical sciences Medium 32210709

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 New gene associations in osteoarthritis: what do they provide, and where are we going? Current opinion in rheumatology 50 17762607
2006 Association between a variation in LRCH1 and knee osteoarthritis: a genome-wide single-nucleotide polymorphism association study using DNA pooling. Arthritis and rheumatism 49 16447229
2017 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration and ameliorates experimental autoimmune encephalomyelitis. The Journal of experimental medicine 40 28028151
2014 Genetic determinants of P wave duration and PR segment. Circulation. Cardiovascular genetics 39 24850809
2014 Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression. Genes, chromosomes & cancer 32 24478024
2021 Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project. Stroke 26 34727735
2016 Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis. Annals of the rheumatic diseases 24 27974301
2020 Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model. Journal of neuroinflammation 19 32631435
2006 Genetic association analysis of LRCH1 as an osteoarthritis susceptibility locus. Rheumatology (Oxford, England) 18 16891653
2007 Lack of association of single nucleotide polymorphism in LRCH1 with knee osteoarthritis susceptibility. Journal of human genetics 15 18049793
2010 Field synopsis and synthesis of genetic association studies in osteoarthritis: the CUMAGAS-OSTEO information system. American journal of epidemiology 13 20237151
2023 Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses. British journal of cancer 11 37365285
2018 Progression Rate Associated Peripheral Blood Biomarkers of Parkinson's Disease. Journal of molecular neuroscience : MN 11 29936662
2020 LRCH1 deficiency enhances LAT signalosome formation and CD8+ T cell responses against tumors and pathogens. Proceedings of the National Academy of Sciences of the United States of America 10 32727906
2020 LRCH1 suppresses migration of CD4+ T cells and refers to disease activity in ulcerative colitis. International journal of medical sciences 9 32210709
2024 Identification of shared genetic etiology of cardiovascular and cerebrovascular diseases through common cardiometabolic risk factors. Communications biology 8 39730871
2019 LRCH1 polymorphisms linked to delayed encephalopathy after acute carbon monoxide poisoning identified by GWAS analysis followed by Sequenom MassARRAY® validation. BMC medical genetics 5 31842790
2020 Leucine rich repeats and calponin homology domain containing 1 inhibits NK-92 cell cytotoxicity through attenuating Src signaling. Immunobiology 2 32173150
2026 Integration of Genome-Wide Association Studies With Single-Cell and Bulk Expression Quantitative Trait Locus to Identify Stroke Susceptibility Genes. Journal of the American Heart Association 0 42003665

Missed literature

Know a paper Affinage missed for LRCH1? Flag it for the maintainers and the community.

No submissions yet.