Myotubularin-related protein 5 (MTMR5)

Myotubularin-related protein 5 (MTMR5), also known as SET-binding factor 1 (SBF1), is a member of the myotubularin family of phosphoinositide phosphatases. Although it belongs to the protein-tyrosine phosphatase superfamily, it is a pseudophosphatase that lacks catalytic activity due to the absence of a conserved active-site cysteine. Instead, MTMR5 functions as a critical regulatory adapter that heterodimerizes with the active phosphatase MTMR2, significantly enhancing its ability to dephosphorylate phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Additionally, MTMR5 acts as a guanine nucleotide exchange factor (GEF) for Rab GTPases, such as Rab28, thereby playing a central role in endosomal trafficking and membrane dynamics (PubMed:12668758, 20937701). In the peripheral nervous system, MTMR5 is essential for proper axon radial sorting and myelination; biallelic loss-of-function mutations in the SBF1 gene cause Charcot-Marie-Tooth disease type 4B3 (CMT4B3), a severe demyelinating neuropathy (PubMed:23847141). Recent studies have also identified MTMR5 as a potent, neuron-enriched suppressor of autophagy that limits the clearance of toxic protein aggregates like TDP-43. This makes MTMR5 a high-interest therapeutic target for neurodegenerative diseases, as its inhibition may sensitize neurons to autophagy induction and promote the degradation of disease-associated proteins (PubMed:35580604). While no direct clinical inhibitors are currently approved, experimental strategies involving VPS34 inhibition or MTMR5 knockdown are being explored to modulate its pathway in disease contexts.

Other names

SET-binding factor 1SBF1hSBF1SBF1p