Affinage

ELMOD2

ELMO domain-containing protein 2 · UniProt Q8IZ81

Length
293 aa
Mass
35.0 kDa
Annotated
2026-06-09
10 papers in source corpus 7 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELMOD2 is a broadly-specific ARF-family GTPase-activating protein (GAP) that coordinates membrane and cytoskeletal dynamics across multiple organelles by acting both as a GAP and as a GTPase effector (PMID:17452337). It was first purified as a GAP for ARL2 that, unusually, also accelerates GTP hydrolysis on ARF proteins despite lacking the canonical ARF-GAP signature, defining an exceptionally broad ARF-family specificity (PMID:17452337). Working downstream of ARL2, ELMOD2 promotes mitofusin-dependent mitochondrial fusion, with ELMOD2, ARL2, MFN1/2, MIRO1/2 and mitoPLD co-localizing at discrete mitochondrial puncta; this fusion-promoting function is retained by a GAP-dead mutant, showing it is GAP-independent (PMID:30865555), and ELMOD2-ARL2 interaction supports the mitochondrial dynamics required for meiotic progression (PMID:28324667). With ARL2 and Rootletin it suppresses spurious ciliation, maintains centrosome cohesion and regulates ciliary vesicle docking, functioning downstream of TTBK2 and upstream of CP110 (PMID:33596093), and with ARL2/TBCD it supports centrosomal microtubule nucleation while separately acting with ARF6 in cytokinesis (PMID:32614697). At lipid droplets, ELMOD2 is anchored by palmitoylation and limits ATGL recruitment, with both its GAP activity and palmitoylation-dependent localization required to control cellular triglyceride levels (PMID:25904333). ELMOD2 is also required for TLR3-dependent type I and III interferon expression in antiviral responses (PMID:19966137).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 High

    Establishing the core biochemical activity: ELMOD2 was identified as a GAP for ARL2 that also acts on ARF proteins, defining it as a broad-specificity ARF-family GAP and the molecular basis for its later roles.

    Evidence Protein purification from bovine testis and in vitro GAP assays against ARL2 and ARF substrates

    PMID:17452337

    Open questions at the time
    • No structural basis for the broad specificity despite lacking the canonical ARF-GAP signature
    • Cellular substrates and physiological contexts not addressed
    • No partners beyond the tested GTPases identified
  2. 2009 Medium

    First cellular role linked ELMOD2 to innate immunity, showing it is required for TLR3-driven antiviral interferon expression.

    Evidence Overexpression and siRNA knockdown in A549 cells and macrophages with microarray, qPCR, and TLR3 activation readouts

    PMID:19966137

    Open questions at the time
    • Molecular step in the TLR3 pathway connecting GAP activity to IFN induction not defined
    • Whether GAP activity or a specific GTPase partner is required not tested
    • Single lab, single cell-type panel
  3. 2015 High

    Defined a lipid-droplet function and the determinants required for it, showing ELMOD2 controls ATGL recruitment and triglyceride levels via palmitoylation-dependent LD localization and GAP activity.

    Evidence siRNA knockdown, GAP-dead and palmitoylation-deficient mutagenesis with siRNA-resistant rescue, triglyceride quantification, immunofluorescence, fractionation

    PMID:25904333

    Open questions at the time
    • The relevant GTPase substrate at lipid droplets not identified in this work
    • Palmitoylation enzyme(s) acting on ELMOD2 unknown
    • Mechanism connecting ELMOD2 to Arf1-COPI not directly demonstrated here
  4. 2017 Medium

    Tied ELMOD2 physically and functionally to ARL2 in mitochondrial dynamics, showing the interaction is required for meiotic progression.

    Evidence Co-immunoprecipitation, co-localization, siRNA knockdown in mouse oocytes with ATP, polar body, and chromosome readouts

    PMID:28324667

    Open questions at the time
    • Single Co-IP without reciprocal or endogenous validation
    • Direct molecular mechanism linking ARL2 interaction to mitochondrial morphology not resolved
    • Whether GAP activity is required for the oocyte phenotype untested
  5. 2019 High

    Resolved the mechanism of ELMOD2 in mitochondrial fusion, showing it acts downstream of ARL2 to promote mitofusin-dependent fusion independently of its GAP activity.

    Evidence CRISPR knockout, overexpression, GAP-dead mutagenesis, photoactivatable-GFP fusion-rate assays, and co-localization with ARL2/MFN1/2/MIRO1/2/mitoPLD

    PMID:30865555

    Open questions at the time
    • The non-catalytic (effector) mechanism by which ELMOD2 promotes fusion not defined
    • Direct interactions with mitofusins or MIRO proteins not established
    • Relationship of the fusion role to the lipid-droplet/ER localization unclear
  6. 2020 Medium

    Demonstrated functional versatility by separating two centrosome/cytokinesis roles tied to distinct GTPase partners (ARL2/TBCD for microtubule nucleation; ARF6 for cytokinesis).

    Evidence ELMOD2 deletion in MEFs with myc-tagged rescue, microtubule nucleation and cytokinesis assays

    PMID:32614697

    Open questions at the time
    • Whether ELMOD2 acts as GAP or effector in each role not fully delineated
    • Direct physical interaction with ARF6 and TBCD not biochemically mapped here
    • Spatial regulation directing ELMOD2 to distinct partners unknown
  7. 2021 High

    Placed ELMOD2 in a defined ciliation-control pathway, showing it acts with ARL2 and Rootletin to suppress spurious ciliation and maintain centrosome cohesion within a TTBK2-to-CP110 axis.

    Evidence ELMOD2 and Rootletin deletion in MEFs, genetic epistasis, rescue by ARL2 activation or Rootletin overexpression, ciliary marker immunofluorescence

    PMID:33596093

    Open questions at the time
    • Direct biochemical interaction among ELMOD2, ARL2, and Rootletin not shown
    • How ELMOD2 GAP activity feeds into Rootletin/rootlet maintenance unresolved
    • Mechanistic link to ciliary vesicle docking not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single broad-specificity GAP is partitioned among mitochondria, lipid droplets, centrosomes, and immune signaling—and when it acts catalytically versus as a non-catalytic effector—remains unresolved.
  • No unifying model for spatial/partner selection across organelles
  • Catalytic versus effector contributions not systematically separated across functions
  • No structural data explaining broad ARF-family specificity

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 3 GO:0005811 lipid droplet 2 GO:0005815 microtubule organizing center 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1430728 Metabolism 1 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1
Partners
ARF6ARL2ATGLMFN1MFN2ROOTLETINTBCD

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 ELMOD2 was purified from bovine testis and identified as a GTPase-activating protein (GAP) for ARL2. It also exhibited GAP activity against ARF proteins despite lacking the canonical ARF GAP sequence signature, demonstrating unusually broad specificity within the ARF family. Protein purification from bovine testis, in vitro GAP activity assay The Journal of biological chemistry High 17452337
2009 ELMOD2 is required for TLR3-dependent type I and type III interferon expression in human alveolar epithelial cells and macrophages. Forced overexpression of ELMOD2 increased IFN mRNA levels, while siRNA knockdown inhibited antiviral cytokine expression upon TLR3 activation. Overexpression cell model (A549), siRNA knockdown, expression microarray, qPCR, TLR3 activation assay FASEB journal Medium 19966137
2015 ELMOD2 is anchored to lipid droplets (LDs) via palmitoylation and regulates ATGL (adipocyte triglyceride lipase) recruitment to LDs. Knockdown of ELMOD2 increased ATGL on LDs and decreased total cellular triglycerides; rescue required both GAP activity and palmitoylation-dependent LD localization. siRNA knockdown, site-directed mutagenesis (GAP-dead and palmitoylation-deficient mutants), triglyceride quantification, rescue with siRNA-resistant constructs Molecular biology of the cell High 25904333
2015 ELMOD2 localizes to lipid droplets, endoplasmic reticulum, and mitochondria. Palmitoylation is specifically required for its distribution to lipid droplets, while LD-deficient palmitoylation mutant fails to reconstitute ATGL transport after ELMOD2 knockdown. Immunofluorescence, palmitoylation-deficient mutagenesis, subcellular fractionation Molecular biology of the cell Medium 25904333
2017 ELMOD2 co-localizes with ARL2 in mouse oocytes and physically interacts with ARL2 (co-immunoprecipitation). ELMOD2 knockdown causes mitochondrial aggregation, reduced ATP levels, meiotic delay, abnormal chromosomal segregation, and aneuploidy, implicating ELMOD2-ARL2 interaction in maintaining mitochondrial dynamics required for meiotic progression. siRNA knockdown in mouse oocytes, co-immunoprecipitation, immunofluorescence co-localization, ATP measurement, polar body extrusion assay, chromosome spread analysis Cell cycle Medium 28324667
2019 ELMOD2 acts downstream of ARL2 to promote mitochondrial fusion in a mitofusin-dependent manner. Loss of ELMOD2 causes mitochondrial fragmentation and reduced fusion rate; overexpression promotes tubulation and increases fusion rate. A GAP-dead mutant of ELMOD2 retains the ability to promote fusion, indicating GAP activity is dispensable for this function. ELMOD2, ARL2, MFN1/2, MIRO1/2, and mitoPLD co-localize at discrete puncta along mitochondria. CRISPR/gene knockout, overexpression, GAP-dead mutagenesis, mitochondrial morphology assay, fusion rate measurement (photoactivatable GFP), immunofluorescence Molecular biology of the cell High 30865555
2020 ELMOD2 acts with ARL2 and TBCD to support microtubule nucleation from centrosomes, and separately acts with ARF6 in cytokinesis. These two functions are separable and linked to distinct GTPase partners, demonstrating that ELMOD2 can serve as both a GAP and an effector for different ARF family GTPases at different cellular locations. ELMOD2 deletion in mouse embryonic fibroblasts (MEFs), rescue with ELMOD2-myc expression, microtubule nucleation assay, cytokinesis analysis Molecular biology of the cell Medium 32614697
2021 ELMOD2 acts in a common pathway with ARL2 and Rootletin to suppress spurious ciliation, maintain centrosome cohesion, and regulate ciliary vesicle docking. Mechanistically, ELMOD2-KO MEFs show increased ciliation, multiciliation, centrin accumulation inside cilia, and loss of rootlets. Epistasis experiments place ELMOD2, Rootletin, and ARL2 downstream of TTBK2 and upstream of CP110. Increasing ARL2 activity or overexpressing Rootletin rescued ELMOD2-deletion phenotypes; deletion of Rootletin yielded similar phenotypes rescued by increasing ARL2 but not ELMOD2 overexpression. ELMOD2 deletion (MEFs), Rootletin deletion, genetic epistasis, rescue by ARL2 activation or Rootletin overexpression, immunofluorescence, ciliary marker analysis Molecular biology of the cell High 33596093

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis. American journal of human genetics 82 16773575
2007 ELMOD2 is an Arl2 GTPase-activating protein that also acts on Arfs. The Journal of biological chemistry 74 17452337
2009 ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 50 19966137
2015 ELMOD2 is anchored to lipid droplets by palmitoylation and regulates adipocyte triglyceride lipase recruitment. Molecular biology of the cell 44 25904333
2019 ELMOD2 regulates mitochondrial fusion in a mitofusin-dependent manner, downstream of ARL2. Molecular biology of the cell 19 30865555
2021 Roles for ELMOD2 and Rootletin in ciliogenesis. Molecular biology of the cell 17 33596093
2020 The ARF GAP ELMOD2 acts with different GTPases to regulate centrosomal microtubule nucleation and cytokinesis. Molecular biology of the cell 13 32614697
2017 GTPase-activating protein Elmod2 is essential for meiotic progression in mouse oocytes. Cell cycle (Georgetown, Tex.) 7 28324667
2020 lncRNA CRNDE is Upregulated in Glioblastoma Multiforme and Facilitates Cancer Progression Through Targeting miR-337-3p and ELMOD2 Axis. OncoTargets and therapy 5 32982309
2025 ELMOD2 Overexpression Predicts Adverse Outcomes and Regulates Tumor Progression in Gliomas. Current medical science 2 40397299

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