WANTED – Dead or alive: Myotubularins, a large disease-associated protein family

Abstract

Myotubularins define a large family of proteins conserved through evolution. Several members are mutated in different neuromuscular diseases including centronuclear myopathies and Charcot-Marie-Tooth (CMT) neuropathies, or are linked to a predisposition to obesity and cancer. While some members have phosphatase activity against the 3-phosphate of phosphoinositides, regulating the phosphorylation status of PtdIns3P and PtdIns(3,5)P implicated in membrane trafficking and autophagy, and producing PtdIns5P, others lack key residues in the catalytic site and are classified as dead-phosphatases. However, these dead phosphatases regulate phosphoinositide-dependent cellular pathways by binding to catalytically active myotubularins. Here we review previous studies on the molecular regulation and physiological roles of myotubularins. We also used the recent myotubularins three-dimensional structures to underline key residues that are mutated in neuromuscular diseases and required for enzymatic activity. In addition, through database mining and analysis, expression profile and specific isoforms of the different myotubularins are described in depth, as well as a revisited protein interaction network. Comparison of the interactome and expression data for each myotubularin highlights specific protein complexes and tissues where myotubularins should have a key regulatory role.

Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

“…In vivo, PIKfyve overexpression results in an increase in PtdIns5 P , whereas PIKfyve +/null heterozygous mice have lower PtdIns5 P levels compared to control mice, without displaying a negative effect on mice viability [68]. The major source of PtdIns5 P in human cells comes from the action of the myotubularins, a family of phosphoinositide 3-phosphatases associated to different diseases: X-linked centronuclear myopathy (MTM1), Charcot-Marie-Tooth CMT4B1 (MTMR2), CMT4B2 (MTMR13) and CMT4B3 (MTMR5) [46,70]. In human cell cultures and in myotubes, the founder member of this family, named myotubularin MTM1, dephosphorylates PtdIns(3,5) P 2 in PtdIns5 P [71].…”

A multicenter, retrospective medical record review of X‐linked myotubular myopathy: The recensus study

“…X‐linked myotubular myopathy (XLMTM) is a centronuclear myopathy caused by pathogenic variants in the MTM1 gene, resulting in a lack or dysfunction of the protein myotubularin . The disorder is rare and primarily affects boys, with an estimated incidence of 1 in 50,000 live male births .…”

A multicenter retrospective study of charcot‐marie‐tooth disease type 4B (CMT4B) associated with mutations in myotubularin‐related proteins (MTMRs)

“…Further subdivision is based mainly on involved genes and loci. 10,37 MTMR2 dephosphorylates PtdIns3P and PtdIns(3,5)P 2 phosphoinositides, which are potent signaling molecules regulating membrane trafficking within the cell. 6 CMT4B includes three clinical and genetically distinct subtypes.…”

“…5 Among demyelinating recessive forms, CMT4B is characterized pathologically by the presence of focal hypermyelination on nerve biopsy, with myelin outfoldings constituted by redundant loops of myelin lamellae involving the vast majority of fibers. 37 MTMR2 can heterodimerize with MTMR13 and MTMR5 through coiled-coil domains. CMT4B1 and CMT4B2 are associated with mutations in the MTMR2 and MTMR13 (myotubularin-related protein 2 and 13, which is also named SET binding factor 2 [SBF2]) genes, respectively.…”

“…Among 14 members, eight are catalytically active phosphatases, whereas six represent catalytically inactive proteins, also called "dead" phosphatases. 10,37 MTMR2 dephosphorylates PtdIns3P and PtdIns(3,5)P 2 phosphoinositides, which are potent signaling molecules regulating membrane trafficking within the cell. On the contrary, MTMR5 and MTMR13, which are highly homologous, are not able to dephosphorylate phospholipids and are thought to assist catalytically active enzymes to properly localize at subcellular membranes and increase their catalytic activity.…”