TM9SF3

TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy (Golgiphagy) receptor, binding all six mammalian ATG8 family proteins through N-terminal LC3-interacting regions (LIR motifs) to target Golgi fragments for lysosomal degradation under nutrient stress and pharmacological Golgi stress, thereby maintaining Golgi integrity and protein glycosylation fidelity (PMID:40609542). TM9SF3 additionally mediates pH-dependent translocation of phosphatidylinositol 4,5-bisphosphate (PIP2) from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification; in zebrafish, loss of Tm9sf3 disrupts PIP2-dependent cytoskeletal organization and collective cell migration during gastrulation (PMID:41053185). TM9SF3 positively regulates cell proliferation and invasion in T-cell leukemia cells and is a direct target of miR-1193 (PMID:28390114).

1. 2017 Medium

   The first functional characterization of TM9SF3 demonstrated it promotes cell proliferation and invasion, positioning it as a potential oncogenic effector, and identified miR-1193 as a direct upstream regulator targeting the TM9SF3 3′UTR.

   Evidence Luciferase reporter assays, siRNA knockdown, and overexpression in Jurkat T-cell leukemia cells

   PMID:28390114

   Open questions at the time

   • Single cell-line system without in vivo validation
   • Molecular mechanism linking TM9SF3 to proliferation and invasion was not determined
   • No identification of downstream effectors or pathways
2. 2025 High

   A genome-wide screen revealed that TM9SF3 mediates pH-dependent PIP2 flop across the plasma membrane, establishing its first defined lipid-handling activity and linking it to cytoskeletal reorganization and collective cell migration in vivo.

   Evidence Genome-wide screening, live-cell PIP2 translocation imaging, extracellular pH manipulation, and zebrafish loss-of-function analysis during gastrulation

   PMID:41053185

   Open questions at the time

   • Whether TM9SF3 acts as a direct lipid flippase or recruits one is unresolved
   • Structural basis of pH-sensing by TM9SF3 is unknown
   • Relationship between PIP2 flop activity and the Golgiphagy receptor function has not been addressed
3. 2025 High

   TM9SF3 was identified as a Golgiphagy receptor that binds all six mammalian ATG8 proteins via N-terminal LIR motifs, providing the first mechanistic explanation for how Golgi fragments are selectively targeted for autophagic degradation and how glycosylation quality control is maintained.

   Evidence CRISPR knockout, overexpression, LIR mutagenesis, co-immunoprecipitation with ATG8 proteins, autophagosome targeting assays, and glycosylation assays with monensin and brefeldin A stress in U2OS cells

   PMID:40609542

   Open questions at the time

   • Whether TM9SF3 cooperates with other Golgi autophagy receptors or acts independently is unclear
   • Physiological consequences of TM9SF3 loss in whole organisms under Golgi-stress conditions have not been reported
   • How TM9SF3 senses glycosylation defects or Golgi damage to trigger its receptor activity is not defined

• It remains unknown how TM9SF3's two established activities — Golgiphagy receptor function and plasma membrane PIP2 translocation — are coordinated or whether they reflect distinct protein pools at different subcellular compartments, and the structural basis for ATG8 binding and pH-dependent lipid handling has not been determined.
• No structural model of TM9SF3 exists
• Whether post-translational modifications regulate the switch between Golgi and plasma membrane functions is unknown
• In vivo mammalian loss-of-function phenotypes have not been characterized