FAM111B

FAM111B is a nuclear trypsin-like serine protease that controls cell cycle progression and cell survival by directly degrading cell-cycle inhibitors and other substrates (PMID:32418298, PMID:40975977). Its catalytic activity drives proliferation: it degrades p16 to permit cyclin D1-CDK4-dependent progression in KRAS-driven lung adenocarcinoma (PMID:32418298), and hydrolyzes the CDK inhibitor P27 via its catalytic triad to activate Cyclin-CDK/RB/E2F1 signaling, raise LDHA transcription, and promote glycolytic metastasis (PMID:40975977). The trypsin protease domain is also required for binding and degradation of GSDMA, an axis that drives esophageal cancer progression and modulates cisplatin sensitivity (PMID:37672204). Beyond direct proteolysis, FAM111B interacts with nucleoporins of the nuclear pore complex and maintains nuclear shape and telomeric DNA content, with its loss producing micronuclei and ultra-fine DNA bridges (PMID:37342232), and it recruits the CTLH E3 ligase subunit RANBP9 to promote MFN2 ubiquitination, thereby controlling mitochondrial fusion, metabolic balance, and mitophagy (PMID:40855067). FAM111B additionally acts as a host restriction factor against DNA viruses, suppressing adenovirus and cytomegalovirus replication from nuclear viral replication compartments (PMID:34071532, PMID:39494906). Dominant missense mutations clustering in the peptidase domain cause hereditary fibrosing poikiloderma with tendon contracture, myopathy and pulmonary fibrosis (POIKTMP) (PMID:24268661), and these variants perturb ubiquitin-proteasome function and drive a sterile type I interferon signature in patient cells (PMID:40840166).

1. 2013 High

   Established FAM111B as a disease gene by linking it to a defined Mendelian multisystem fibrosing syndrome, and pinpointed its likely catalytic identity through mutation clustering.

   Evidence Whole-exome sequencing and segregation analysis across POIKTMP pedigrees

   PMID:24268661

   Open questions at the time

   • No enzymatic assay confirming protease activity
   • Mechanism by which mutations cause multisystem fibrosis unknown
   • No substrate identified
2. 2015 Medium

   Reinforced that pathogenic variants concentrate in the trypsin-like peptidase domain, framing disease as a gain-of-function or dominant-negative alteration of enzymatic activity.

   Evidence Domain mapping of missense variants across 10 independent families

   PMID:26471370

   Open questions at the time

   • No direct enzymatic measurement
   • Gain-of-function vs dominant-negative not distinguished biochemically
3. 2020 Medium

   Provided the first mechanistic function by showing FAM111B drives cell cycle progression through degradation of the CDK4 inhibitor p16, placing it in proliferative signaling.

   Evidence FAM111B-knockout cell lines with proliferation/cell-cycle assays and p16/cyclin D1-CDK4 immunoblotting

   PMID:32418298

   Open questions at the time

   • Direct proteolysis of p16 not biochemically reconstituted
   • Single tumor context (KRAS lung adenocarcinoma)
4. 2021 Medium

   Identified FAM111B as an antiviral host restriction factor whose levels are actively counteracted by viral oncoproteins, expanding its role beyond proliferation.

   Evidence shRNA knockdown and adenovirus replication assays implicating E1B-55K/E4orf6

   PMID:34071532

   Open questions at the time

   • Molecular mechanism of restriction unknown
   • Whether protease activity is required not tested
5. 2022 Medium

   Showed FAM111B expression is epigenetically silenced, defining upstream transcriptional control via promoter methylation.

   Evidence ChIP for DNMT3B promoter binding plus methylation and functional assays in thyroid cancer

   PMID:35864964

   Open questions at the time

   • Downstream FAM111B effector in this context not defined
   • Single cancer type
6. 2023 Medium

   Connected FAM111B to nuclear architecture and genome stability, demonstrating physical association with the nuclear pore complex and a role in telomere maintenance.

   Evidence Co-IP with nucleoporins, nuclear imaging, telomere FISH/qPCR and micronuclei assays in U2OS/MCF7 cells

   PMID:37342232

   Open questions at the time

   • Specific nucleoporin partners not resolved
   • Mechanism linking protease activity to telomere maintenance unknown
   • Single lab
7. 2023 Medium

   Demonstrated that the trypsin protease domain is required for degrading a specific substrate (GSDMA), directly tying catalytic function to tumor phenotypes and drug response.

   Evidence Co-IP, trypsin-domain mutagenesis, RNA-seq and xenografts in esophageal cancer

   PMID:37672204

   Open questions at the time

   • Cleavage site on GSDMA not mapped
   • In vitro proteolysis not reconstituted
8. 2024 Medium

   Extended antiviral function to herpesviruses and identified an activating transcription factor, distinguishing FAM111B from its paralog FAM111A.

   Evidence CRISPR knockout and shRNA with MCMV replication readouts, transcriptome analysis, and immunofluorescence of viral replication compartments

   PMID:39494906

   Open questions at the time

   • Restriction mechanism within replication compartments undefined
   • Role of protease activity not tested
9. 2025 Medium

   Defined a non-proteolytic adaptor function in which FAM111B recruits an E3 ligase to control mitochondrial dynamics and metabolism.

   Evidence Co-IP of FAM111B-RANBP9, MFN2 stability assays, mitochondrial imaging and metabolic flux assays with xenografts

   PMID:40855067

   Open questions at the time

   • Whether MFN2 ubiquitination requires FAM111B catalytic activity unclear
   • Direct vs scaffold role in ligase recruitment not separated
10. 2025 Medium

    Provided direct biochemical evidence of FAM111B protease activity by showing catalytic-triad-dependent hydrolysis of P27 driving a glycolytic, pro-metastatic program.

    Evidence In vitro hydrolysis assay with hydrolytic triad, transcriptomic/proteomic analysis and in vivo metastasis assays in prostate cancer

    PMID:40975977

    Open questions at the time

    • Cleavage site on P27 not mapped
    • Full substrate repertoire unknown
11. 2025 Medium

    Linked disease-causing variants to a molecular pathology in patients, showing UPS dysfunction and a sterile interferon signature that scales with mutation location.

    Evidence Multi-omics of patient-derived cells, ubiquitin conjugate assays and interferon signature analysis in a 41-patient POIKTMP cohort

    PMID:40840166

    Open questions at the time

    • Causal chain from variant protease change to UPS perturbation undefined
    • Trigger of interferon signature unknown

• How FAM111B catalytic activity, substrate selection, nuclear pore association, and E3-ligase scaffolding are coordinated — and how disease mutations mechanistically alter these functions to produce multisystem fibrosis — remains unresolved.
• No structure of FAM111B or substrate-bound complex
• Full physiological substrate repertoire unknown
• Mechanistic basis of tissue-specific POIKTMP pathology unestablished