Affinage

FAM98A

Protein FAM98A · UniProt Q8NCA5

Length
518 aa
Mass
55.3 kDa
Annotated
2026-06-09
21 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM98A is a multifunctional scaffolding protein that operates within the RTCB-containing tRNA ligase complex and partitions that machinery to the cytoplasm [PMID:bio_10.1101_2025.08.01.668163]. Through compositional control, FAM98A defines a form of the tRNA ligase complex that lacks the nuclear import factor Ashwin, retaining the assembly in the cytoplasm rather than directing it to the nucleus for pre-tRNA splicing; this is rationalized structurally by its paralog FAM98B forming a co-folded heterodimer with CGI-99 that clamps Ashwin, an architecture FAM98A-containing complexes do not adopt [PMID:bio_10.1101_2025.08.01.668197, PMID:bio_10.1101_2025.08.01.668163]. FAM98A is a direct PRMT1 substrate, and arginine dimethylation at defined sites is required for its role in promoting cell migration, since dimethylation-deficient mutants phenocopy FAM98A loss (PMID:26503212, PMID:36757215). FAM98A also forms a complex with DDX1 and C14orf166 together with FAM98B and is required to sustain PRMT1 expression and proliferation in cancer cells (PMID:28040436). Upon cellular stress, FAM98A localizes to stress granules via its C-terminal low-complexity region, where it scaffolds DDX1, ATXN2, ATXN2L, and NUFIP2 and supports stress granule assembly (PMID:29992460). In osteoclasts, FAM98A associates with PLEKHM1 and NDEL1 to couple lysosomes to microtubules for peripheral lysosome positioning and bone resorption (PMID:27777970), though conditional Fam98a knockout in mice does not impair bone resorption owing to compensatory upregulation of Fam98b (PMID:39857276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 Medium

    Established FAM98A as a post-translationally regulated effector of cell motility by identifying it as a PRMT1 methylation substrate with a migration/invasion phenotype.

    Evidence In vitro PRMT1 methylation assay and siRNA knockdown with migration, invasion, and colony formation readouts in ovarian cancer cells

    PMID:26503212

    Open questions at the time
    • Specific methylated residues not yet mapped
    • Mechanistic link between methylation and migration not defined
    • Single cell-type context
  2. 2016 Medium

    Placed FAM98A in a stable cytoplasmic complex (DDX1-C14orf166-FAM98A/B) and linked it to maintenance of PRMT1 expression and proliferation, connecting the scaffold to its own upstream modifier.

    Evidence Co-immunoprecipitation, siRNA knockdown with proliferation/colony assays, and TCGA correlation in colorectal cancer cells

    PMID:28040436

    Open questions at the time
    • How the complex regulates PRMT1 levels mechanistically unclear
    • Direct vs indirect effect on PRMT1 not resolved
  3. 2016 Medium

    Defined a membrane-trafficking role for FAM98A by showing it bridges lysosomes to microtubules within a PLEKHM1/DEF8/RAB7/NDEL1 complex governing lysosome positioning and bone resorption.

    Evidence Co-IP/interaction mapping and siRNA knockdown with lysosome distribution and bone resorption readouts in osteoclasts

    PMID:27777970

    Open questions at the time
    • Direct binding interface within the complex not mapped
    • Whether this role is osteoclast-specific unknown
  4. 2018 Medium

    Identified FAM98A as a stress granule component and assembly factor, mapping the responsible domain and its RNA-granule partners.

    Evidence Fluorescence microscopy, C-terminal low-complexity deletion mutants, siRNA knockdown of granule number, and co-IP of DDX1/ATXN2/ATXN2L/NUFIP2

    PMID:29992460

    Open questions at the time
    • RNA targets within granules not identified
    • Role of phase separation vs protein-protein scaffolding unresolved
  5. 2018 Low

    Proposed a P38-ATF2 signaling axis downstream of FAM98A in lung cancer proliferation.

    Evidence Overexpression/knockdown in NSCLC lines with Western blotting and pharmacological P38 inhibition

    PMID:30100758

    Open questions at the time
    • No direct FAM98A-P38 interaction demonstrated
    • Pathway placement inferred from OE and inhibitor only
    • Single lab
  6. 2022 Low

    Linked FAM98A stress-granule function to chemoresistance via xCT translational control and ferroptosis inhibition.

    Evidence Overexpression/knockdown, immunoblotting, immunoprecipitation, and in vitro/in vivo proliferation assays in colorectal cancer cells

    PMID:35421356

    Open questions at the time
    • xCT translation regulation not reconstituted
    • Direct vs indirect role in ferroptosis unclear
    • Single lab
  7. 2023 Medium

    Resolved how PRMT1 modification controls FAM98A by mapping five arginine dimethylation sites and demonstrating their functional requirement for migration.

    Evidence mNeuCode metabolic labeling, targeted MS/MS, site-directed mutagenesis, and migration assays in FAM98A-KO HeLa cells

    PMID:36757215

    Open questions at the time
    • Downstream effectors of dimethylated FAM98A unknown
    • Whether methylation affects complex assembly or localization untested
  8. 2025 High

    Established FAM98A as a compositional determinant of tRNA ligase complex identity and cytoplasmic localization by showing FAM98A-containing complexes lack Ashwin and are retained in the cytoplasm, with cryo-EM providing the structural rationale.

    Evidence Cryo-EM structure of the tRNA-LC, structure-based mutagenesis, biochemical fractionation, and NLS disruption/rescue with pre-tRNA splicing assays (two preprints from different labs)

    PMID:bio_10.1101_2025.08.01.668163 PMID:bio_10.1101_2025.08.01.668197

    Open questions at the time
    • Cytoplasmic substrate/function of the FAM98A-tRNA-LC not fully defined
    • Peer review pending (preprints)
    • Functional distinction from FAM98C-containing complex unclear
  9. 2025 Medium

    Tested the in vivo requirement for FAM98A in bone, revealing functional redundancy with FAM98B.

    Evidence Myeloid-specific conditional Fam98a knockout mice, shRNA knockdown, osteoclastogenesis and bone resorption assays, and micro-CT

    PMID:39857276

    Open questions at the time
    • Extent of FAM98A/FAM98B functional overlap in other tissues unknown
    • Whether compensation occurs outside osteoclasts untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific cytoplasmic RNA-processing function unique to the FAM98A-defined tRNA ligase complex, and how its PRMT1 dimethylation and stress-granule recruitment integrate with this role, remain unresolved.
  • No defined catalytic or substrate-specific output unique to FAM98A complexes
  • Connection between methylation, stress granules, and tRNA-LC roles not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 2
Complex memberships
DDX1-C14orf166-FAM98A/B complexPLEKHM1/DEF8/RAB7/FAM98A/NDEL1 lysosome-microtubule complexRTCB-containing tRNA ligase complexstress granule

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 FAM98A binds to PLEKHM1 and, together with NDEL1, connects lysosomes to microtubules. This PLEKHM1/DEF8/RAB7/FAM98A/NDEL1 complex regulates peripheral lysosome positioning and secretion in osteoclasts; knockdown of FAM98A phenocopies lysosome positioning and bone resorption defects seen in Plekhm1-null osteoclasts. Co-immunoprecipitation/interaction analysis, siRNA knockdown with lysosome distribution and bone resorption phenotypic readouts in osteoclasts JCI insight Medium 27777970
2015 FAM98A is a substrate of PRMT1 (protein arginine methyltransferase 1); PRMT1 arginine-methylates FAM98A, and FAM98A is required for tumor cell migration, invasion, and colony formation in ovarian cancer cells. In vitro methylation assay (PRMT1 substrate screen), siRNA knockdown with migration/invasion/colony formation assays Tumour biology Medium 26503212
2016 FAM98A and FAM98B form a complex with DDX1 and C14orf166 (DDX1-C14orf166-FAM98A/B complex); this complex is required for PRMT1 expression, and knockdown of FAM98A suppresses PRMT1 levels, proliferation, and colony formation in colorectal cancer cells. Co-immunoprecipitation, siRNA knockdown with proliferation and colony formation assays, TCGA correlation analysis The international journal of biochemistry & cell biology Medium 28040436
2018 FAM98A localizes to stress granules (but not P-bodies) upon various stress stimuli; its C-terminal low-complexity region is required for this localization; FAM98A depletion reduces the number of stress granules per cell; FAM98A associates with stress granule proteins DDX1, ATXN2, ATXN2L, and NUFIP2. Fluorescence microscopy (live imaging/immunofluorescence), deletion mutant analysis, siRNA knockdown, co-immunoprecipitation Molecular and cellular biochemistry Medium 29992460
2018 FAM98A overexpression activates the P38-ATF2 signaling pathway, increasing phospho-P38, phospho-ATF2, and cyclin D1 levels, thereby promoting lung cancer cell proliferation; a P38-specific inhibitor reverses FAM98A overexpression effects. Overexpression and siRNA knockdown in NSCLC cell lines, Western blotting for pathway components, pharmacological inhibition of P38 Cancer management and research Low 30100758
2022 FAM98A promotes resistance to 5-fluorouracil in colorectal cancer cells by inhibiting ferroptosis through activation of xCT translation in stress granules. Overexpression/knockdown, immunoblotting, immunoprecipitation to identify FAM98A-SG association and xCT pathway activation, in vitro and in vivo proliferation assays Archives of biochemistry and biophysics Low 35421356
2023 Five novel arginine dimethylation sites on FAM98A were identified by targeted proteomics; dimethylation-deficient mutation of FAM98A suppressed cell migration to the same extent as FAM98A deletion, indicating that PRMT1-mediated dimethylation of these sites mediates FAM98A's role in cell migration. Metabolic stable-isotope labeling (mNeuCode), targeted MS/MS, site-directed mutagenesis of dimethylation sites, cell migration assay in FAM98A-KO HeLa cells Analytical chemistry Medium 36757215
2025 FAM98A assembles with RTCB (the catalytic tRNA ligase subunit) and other subunits into a compositionally distinct tRNA ligase complex that lacks Ashwin, distinguishing it from the FAM98B-containing nuclear complex; cryo-EM structure of the tRNA-LC shows FAM98B (the paralog) forms an intricately co-folded heterodimer with CGI-99 that clamps Ashwin, providing a structural rationale for why FAM98A- and FAM98C-containing complexes lack Ashwin and may have distinct cellular functions. Cryo-EM (atomic-resolution reconstruction), structure-based mutagenesis, interaction analysis of tRNA-LC subunits bioRxiv (preprint)preprint High bio_10.1101_2025.08.01.668197
2025 FAM98A defines one of three compositionally distinct RTCB-containing tRNA ligase complex forms (FAM98A-, FAM98B-, or FAM98C-containing); FAM98A-containing complexes lack Ashwin (the nuclear import factor), so FAM98A-associated complexes are retained in the cytoplasm rather than being imported to the nucleus, establishing FAM98A as a determinant of cytoplasmic tRNA-LC localization. Biochemical fractionation, interaction assays, NLS disruption/rescue experiments, pre-tRNA splicing assays bioRxiv (preprint)preprint High bio_10.1101_2025.08.01.668163
2025 Conditional knockout of Fam98a in myeloid osteoclast precursors does not reduce trabecular or cortical bone mass in mice, nor does it impair osteoclastogenesis or bone resorption in vitro, apparently because Fam98b expression is upregulated to compensate; in contrast, knockdown of Fam98b in osteoclasts disrupts lysosome trafficking and bone resorption with phenotypes similar to Fam98a knockdown (negative result for in vivo FAM98A loss-of-function). Myeloid-specific conditional Fam98a knockout mice, shRNA knockdown, osteoclastogenesis assays, bone resorption assays, micro-CT bone mass measurement Biology Medium 39857276

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI insight 76 27777970
2018 Differential long noncoding RNA expressions in peripheral blood mononuclear cells for detection of acute ischemic stroke. Clinical science (London, England : 1979) 50 29997237
2013 A divergent calponin homology (NN-CH) domain defines a novel family: implications for evolution of ciliary IFT complex B proteins. Bioinformatics (Oxford, England) 37 24257188
2016 FAM98A associates with DDX1-C14orf166-FAM98B in a novel complex involved in colorectal cancer progression. The international journal of biochemistry & cell biology 33 28040436
2015 FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 26503212
2022 FAM98A promotes resistance to 5-fluorouracil in colorectal cancer by suppressing ferroptosis. Archives of biochemistry and biophysics 31 35421356
2018 FAM98A is localized to stress granules and associates with multiple stress granule-localized proteins. Molecular and cellular biochemistry 17 29992460
2021 MicroRNA-26a inhibits cell proliferation and invasion by targeting FAM98A in breast cancer. Oncology letters 15 33747224
2021 Circular RNA intraflagellar transport 80 facilitates endometrial cancer progression through modulating miR-545-3p/FAM98A signaling. Journal of gynecologic oncology 15 34783205
2019 FAM98A promotes cancer progression in endometrial carcinoma. Molecular and cellular biochemistry 12 31114934
2018 FAM98A promotes proliferation of non-small cell lung cancer cells via the P38-ATF2 signaling pathway. Cancer management and research 12 30100758
2022 Identification of key serum biomarkers for the diagnosis and metastatic prediction of osteosarcoma by analysis of immune cell infiltration. Cancer cell international 8 35151325
2023 mNeuCode Empowers Targeted Proteome Analysis of Arginine Dimethylation. Analytical chemistry 7 36757215
2017 GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing 7 27896979
2021 Emerging Impact of Non-coding RNAs in the Pathology of Stroke. Frontiers in aging neuroscience 6 34867304
2025 Genome-wide CRISPR screen reveals host factors for gama- and delta-coronavirus infection in Huh7 cells. International journal of biological macromolecules 4 39920943
2026 A deep learning and large language hybrid workflow for omics interpretation. Nature biomedical engineering 1 41507521
2025 FAM98 Family Proteins Play Distinct Roles in Osteoclastogenesis and Bone Resorption. Biology 1 39857276
2024 Protein Signatures of Parathyroid Adenoma according to Tumor Volume and Functionality. Endocrinology and metabolism (Seoul, Korea) 1 38509667
2023 Genomic association using principal components of morphometric traits in horses: identification of genes related to bone growth. Animal biotechnology 1 37184429
2025 Kaempferol regulates Ewing sarcoma progression via miR-26b-5p-mediated expression of the family with sequence similarity 98 member A. BMC pharmacology & toxicology 0 41102786

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