TMEM150A

TMEM150A is a multi-pass plasma membrane protein that functions in the homeostatic control of phosphoinositide levels at the plasma membrane as a mammalian functional homologue of yeast Sfk1 (PMID:25608530). It acts within the EFR3–PI4KIIIα machinery: TMEM150A strongly reduces the association of TTC7 with the EFR3–PI4KIIIα complex without disrupting PI4KIIIα localization, revealing plasticity in the interactions that govern this kinase complex (PMID:25608530). This TMEM150A-dependent complex is dedicated to rapid PI(4,5)P2 resynthesis following phospholipase C signaling, and its assembly is controlled by differential palmitoylation of a tri-cysteine motif in EFR3B, with palmitoyl-group spacing dictating both EFR3B–TMEM150A interaction and EFR3B partitioning between liquid-ordered and liquid-disordered membrane regions (PMID:34569608). Through this control of plasma membrane PI(4,5)P2, TMEM150A modulates TLR4-driven cytokine output (PMID:35834652), and it has additionally been characterized as a nutrient-responsive DRAM-family member (DRAM5) acting in autophagic flux under nutrient deprivation (PMID:40396042). The yeast homologue Sfk1p further links this protein family to negative regulation of transbilayer phospholipid movement independent of PI4-kinase activity (PMID:29540528); whether mammalian TMEM150A retains this lipid-scrambling-control function has not been characterized in the available corpus.

1. 2000 Medium

   Established the basic membrane architecture and subcellular address of the protein family, framing it as an integral membrane protein rather than a soluble factor.

   Evidence Topology prediction and EGFP-fusion fluorescence microscopy of rat ortholog TM6P1

   PMID:10858565

   Open questions at the time

   • No functional consequence of localization tested
   • Six-TM topology predicted, not experimentally resolved
2. 2015 High

   Defined TMEM150A's molecular function by showing it is a functional Sfk1 homologue that remodels the EFR3–PI4KIIIα complex by displacing TTC7, placing it in phosphoinositide homeostasis at the plasma membrane.

   Evidence Functional homology rescue, reciprocal co-immunoprecipitation, and PI(4,5)P2 homeostasis readouts in mammalian cells

   PMID:25608530

   Open questions at the time

   • Mechanism by which TMEM150A displaces TTC7 not resolved structurally
   • Stoichiometry of TMEM150A in the complex unknown
3. 2018 Medium

   Revealed via the yeast ortholog a PI4-kinase-independent activity of the family — negative regulation of transbilayer phospholipid movement and membrane permeability — broadening its potential roles beyond phosphoinositide kinase scaffolding.

   Evidence Genetic epistasis (sfk1Δ lem3Δ), lipid exposure assays, permeability and ergosterol measurements in yeast

   PMID:29540528

   Open questions at the time

   • Demonstrated only in yeast, not mammalian TMEM150A
   • Molecular basis of phospholipid movement control unidentified
4. 2021 High

   Showed how complex assembly is regulated, establishing an EFR3B palmitoylation code that gates TMEM150A binding and directs a distinct PI4KIIIα complex toward rapid PI(4,5)P2 resynthesis after PLC signaling.

   Evidence EFR3B cysteine palmitoylation mutagenesis, co-immunoprecipitation, PI(4,5)P2 resynthesis assay, and membrane domain fractionation

   PMID:34569608

   Open questions at the time

   • Enzymes setting the palmitoylation code not identified
   • How TMEM150A senses membrane domain partitioning unknown
5. 2022 Low

   Connected TMEM150A's phosphoinositide function to a physiological output by linking its loss to elevated TLR4-driven cytokine production.

   Evidence siRNA knockdown with LPS stimulation and cytokine ELISA/transcript quantification in epithelial cells

   PMID:35834652

   Open questions at the time

   • Single knockdown approach without rescue
   • Direct mechanistic placement relative to TLR4 inferred from prior PI(4,5)P2 work, not demonstrated
6. 2022 Low

   Assigned TMEM150A to the DRAM autophagy-modulator family (DRAM5) acting in autophagic flux under nutrient stress, implicating it in a second cellular program.

   Evidence Characterization of DRAM family members under nutrient deprivation with autophagic flux assays (commentary/brief report)

   PMID:40396042

   Open questions at the time

   • Limited methodological detail
   • Relationship between autophagy role and PI(4,5)P2 function not established

• Whether the mammalian TMEM150A protein directly regulates transbilayer phospholipid movement, and how its phosphoinositide, TLR4, and autophagy roles mechanistically interrelate, remains open.
• No structural model of TMEM150A within the EFR3–PI4KIIIα complex
• No mammalian demonstration of lipid-scrambling control
• Unified mechanism linking distinct phenotypes not established