TMEM147

TMEM147 is a conserved multi-pass transmembrane protein resident at the endoplasmic reticulum and nuclear envelope that organizes membrane protein complexes governing ER architecture, sterol homeostasis, and nuclear envelope integrity (PMID:20538592, PMID:32694168). It was first identified as a core subunit of the Nicalin-NOMO complex, where assembly is hierarchical and interdependent among the three components, with a topology resembling the gamma-secretase subunit APH-1 (PMID:20538592). At the inner nuclear membrane TMEM147 physically interacts with and anchors lamin B receptor (LBR), and its loss reduces LBR levels and mislocalizes LBR to the ER with abnormal nuclear segmentation (PMID:32694168, PMID:36044892). In parallel, TMEM147 binds and stabilizes the sterol reductase DHCR7 and coordinates LBR/DHCR7 expression, such that its depletion alters cellular cholesterol, cholesteryl ester profiles, and cholesterol uptake (PMID:32694168). TMEM147 also functions within the ribosome-associated TMCO1 translocon complex to facilitate translation of nascent polypeptides, and its loss accelerates protein degradation through the autophagy-lysosomal pathway and remodels the ER toward flat-ER morphology (upregulation of CLIMP-63/CKAP4 and RTN4) (PMID:34638576, PMID:36044892). Bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability in humans (PMID:36044892).

1. 2010 High

   Established TMEM147 as a bona fide protein rather than an orphan transmembrane ORF by placing it as an interdependent core subunit of the Nicalin-NOMO complex at the ER.

   Evidence Affinity purification/mass spectrometry plus overexpression and knockdown in cultured cells, with subcellular localization

   PMID:20538592

   Open questions at the time

   • Did not define a catalytic or signaling output for the complex
   • APH-1-like topology was inferred, not structurally resolved
   • Role of the complex in Nodal signaling not directly tested here
2. 2016 Medium

   Addressed whether TMEM147 has surface/immunomodulatory roles by showing it binds a parasite galectin and mediates proliferation, apoptosis, and cytokine transcription in immune cells.

   Evidence Yeast two-hybrid, Co-IP, RNAi and functional assays in goat PBMC (non-mammalian host-parasite system)

   PMID:27337943

   Open questions at the time

   • Performed in a host-parasite context with a parasitic ligand, limiting generalization to human biology
   • Reported plasma membrane localization conflicts with ER/nuclear envelope localization in mammalian cells
   • No mechanism linking galectin binding to downstream signaling defined
3. 2020 High

   Identified the nuclear-envelope and sterol-regulatory functions of TMEM147 by demonstrating physical interactions with LBR and DHCR7 and their loss-of-function consequences.

   Evidence Reciprocal Co-IP, siRNA silencing, confocal microscopy, western blotting, and lipidomics in HeLa cells

   PMID:32694168

   Open questions at the time

   • Did not resolve whether cholesterol changes are direct (stabilization) or transcriptional
   • Structural basis of the LBR C-terminus interaction not determined
   • No in vivo validation
4. 2021 Medium

   Linked TMEM147 loss to a defined ER morphological shift, connecting its molecular interactions to organelle-scale architecture.

   Evidence siRNA silencing with quantitative immunofluorescence of ER markers RTN4 and CLIMP63 plus interactor network analysis

   PMID:34638576

   Open questions at the time

   • Network functional assignments are computational, not experimentally tested
   • Causal link between ER reshaping and DNA condensation change unresolved
   • Single-lab observation
5. 2022 High

   Established TMEM147 as a disease gene and integrated its roles by showing bi-allelic loss-of-function causes syndromic intellectual disability through LBR anchoring and TMCO1-translocon-dependent translation.

   Evidence Patient fibroblasts (LBR localization, ER markers), neutrophil morphology, in silico structural modeling, and in vitro protein degradation assays across 23 individuals from 15 families

   PMID:36044892

   Open questions at the time

   • Translocon contribution inferred from modeling rather than direct biochemical reconstitution
   • Mechanism connecting molecular defects to neurodevelopmental phenotype not established
   • Substrate specificity of TMEM147 in the translocon not defined
6. 2023 Medium

   Extended the DHCR7 axis to disease physiology by showing TMEM147 promotes DHCR7 via STAT2 and drives a 27-hydroxycholesterol-dependent program affecting ferroptosis resistance and macrophage polarization in hepatocellular carcinoma.

   Evidence Co-IP/MS, RNA-seq, lipidomics, ELISA, ferroptosis and macrophage phenotyping assays, in vitro and in vivo tumor models

   PMID:37891677

   Open questions at the time

   • Multi-step mechanistic chain has indirect links (STAT2, 27HC, GPX4, PPARgamma)
   • Single-lab findings in a cancer context
   • Direct versus indirect control of DHCR7 transcription versus stability not disentangled

• How TMEM147 mechanistically couples its translocon role to substrate-specific biogenesis of multipass membrane proteins, and how this connects to the neurodevelopmental phenotype, remains unresolved.
• No reconstituted structure of TMEM147 within the TMCO1 translocon
• No defined substrate set whose biogenesis depends on TMEM147
• Causal path from molecular defects to intellectual disability not established