TMEM98

TMEM98 is a membrane-associated transmembrane protein whose best-characterized role is the negative regulation of the membrane-bound transcription factor MYRF, acting across both myelinating and ocular contexts (PMID:30249802, PMID:32236127). TMEM98 physically binds the C-terminal domain of MYRF and inhibits MYRF autoproteolytic self-cleavage, thereby preventing nuclear translocation of the activating MYRF N-fragment and downstream target-gene induction; forced TMEM98 expression suppresses oligodendrocyte differentiation and MYRF-driven ectopic myelin gene expression (PMID:30249802). In the retinal pigment epithelium, RPE-specific loss of Tmem98 leads to ectopic nuclear MYRF and grossly enlarged, fragile eyes, establishing TMEM98 as a brake on MYRF activity in eye-size determination (PMID:32236127). Disease-relevant missense mutations modelling human nanophthalmos act as hypomorphic/dominant-negative alleles that disrupt retinal laminar integrity, and structural modelling localizes these mutations to a C-terminal charge-polarized helix (α8) required for function (PMID:31266059, PMID:33596443). Beyond the MYRF axis, TMEM98 binds and destabilizes the GSK3-binding protein FRAT2 to dampen β-catenin/TCF (Wnt) signalling and recycles between the plasma membrane and Golgi (PMID:31961879), and modulates AKT/GSK3β/Cyclin D1 signalling in vascular cells (PMID:32893666, PMID:29152140).

1. 2018 High

   Established that TMEM98 is not merely a structural membrane protein but a direct biochemical regulator of MYRF, answering how oligodendrocyte differentiation might be held in check.

   Evidence Co-IP showing binding to the MYRF C-terminal domain plus overexpression in embryonic chicken spinal cord with Western blot for self-cleavage products and nuclear translocation

   PMID:30249802

   Open questions at the time

   • Stoichiometry and structural basis of the TMEM98–MYRF interaction not resolved
   • Whether inhibition occurs at the membrane prior to cleavage versus by sequestration not distinguished
2. 2019 High

   Defined the in vivo consequences of TMEM98 missense mutations, showing they are hypomorphic/dominant-negative alleles affecting retinal integrity rather than producing the small-eye phenotype seen in human nanophthalmos.

   Evidence Genetic mapping of the Rwhs allele and CRISPR knock-in of human nanophthalmos mutations in mouse, with histology, EM and ERG

   PMID:31266059

   Open questions at the time

   • Molecular mechanism linking the mutations to MYRF dysregulation not directly demonstrated in this study
   • Species difference (no small eyes in mice vs. human nanophthalmos) unexplained
3. 2020 High

   Demonstrated the physiological MYRF-inhibitory role in vivo through tissue-specific loss of function, answering whether TMEM98 restrains MYRF activity in a native epithelium.

   Evidence RPE-specific conditional knockout with BioID proximity labelling, immunofluorescence for MYRF nuclear localization and ocular phenotyping

   PMID:32236127

   Open questions at the time

   • Identity of MYRF target genes driving the enlarged-eye phenotype not defined
   • How loss of MYRF restraint translates to scleral/choroidal thinning mechanistically unresolved
4. 2020 Medium

   Extended TMEM98 function beyond MYRF by identifying a role in Wnt pathway regulation and characterizing its trafficking itinerary.

   Evidence Co-IP for FRAT2 interaction, β-catenin/TCF luciferase reporter, Western blot for FRAT2 levels, and live-cell imaging of plasma membrane–Golgi recycling

   PMID:31961879

   Open questions at the time

   • Mechanism by which TMEM98 lowers FRAT2 protein levels (degradation vs. synthesis) not established
   • Single-lab finding without reciprocal in vivo validation
   • Relationship between Wnt regulation and the MYRF axis unknown
5. 2020 Medium

   Implicated TMEM98 in vascular cell proliferation and inflammatory adhesion signalling, broadening its functional reach.

   Evidence siRNA knockdown in VSMCs and ECs with Western blot for AKT/GSK3β/Cyclin D1 and ICAM-1/VCAM-1, migration/proliferation assays and AKT agonist rescue

   PMID:29152140 PMID:32893666

   Open questions at the time

   • Direct molecular target of TMEM98 upstream of AKT not identified
   • Whether the PDGF-BB feedback loop is direct or indirect unresolved
6. 2020 Medium

   Revealed a protein-independent function in which TMEM98 mRNA itself acts as a regulatory RNA, a distinct mechanism from the canonical transmembrane protein.

   Evidence RIP and RNA pull-down with wild-type and motif-mutated transcripts plus knockdown/overexpression in gastric cancer cells

   PMID:32379372

   Open questions at the time

   • Single-lab finding concerning the mRNA, not the protein; needs orthogonal confirmation
   • Whether mRNA-mediated NF90 regulation operates in non-cancer tissues unknown
7. 2021 Low

   Provided a structural framework localizing nanophthalmos mutations to a specific C-terminal helix, rationalizing why these residues are functionally critical.

   Evidence Protein homology modelling with in vitro confirmation of transmembrane topology

   PMID:33596443

   Open questions at the time

   • Homology model without experimental structure determination or mutagenesis validation
   • Functional consequence of α8 disruption on MYRF binding not tested

• How TMEM98 mechanistically integrates its MYRF, Wnt/FRAT2, and AKT/GSK3β activities, and whether they reflect one unified biochemical action or independent functions, remains unresolved.
• No structure of TMEM98 in complex with any partner
• Mechanism of MYRF self-cleavage inhibition at atomic resolution unknown
• Whether membrane trafficking gates partner access not established