Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8.
The myotubularins are a large family of inositol polyphosphate 3-phosphatases that, despite having common substrates, subsume unique functions in cells that are disparate. The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity, dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P(2)] at the D-3 position. Seven members are inactive because they lack the conserved cysteine residue in the CX(5)R motif required for activity. We studied a subfamily of homologous myotubularins, including myotubularin-related protein 6 (MTMR6), MTMR7, and MTMR8, all of which dimerize with the catalytically inactive MTMR9. Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity, wherein the MTMR6/R9 complex prefers PtdIns(3,5)P(2) as substrate; the MTMR8/R9 complex prefers PtdIns(3)P. MTMR9 increased the enzymatic activity of MTMR6 toward PtdIns(3,5)P(2) by over 30-fold, and enhanced the activity toward PtdIns(3)P by only 2-fold. In contrast, MTMR9 increased the activity of MTMR8 by 1.4-fold and 4-fold toward PtdIns(3,5)P(2) and PtdIns(3)P, respectively. In cells, the MTMR6/R9 complex significantly increases the cellular levels of PtdIns(5)P, the product of PI(3,5)P(2) dephosphorylation, whereas the MTMR8/R9 complex reduces cellular PtdIns(3)P levels. Consequentially, the MTMR6/R9 complex serves to inhibit stress-induced apoptosis and the MTMR8/R9 complex inhibits autophagy.
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Jun
J
Zou
Chunfen
C
Zhang
Jasna
J
Marjanovic
Marina V
MV
Kisseleva
Philip W
PW
Majerus
Monita P
MP
Wilson
D001343:Autophagy / Q000502:physiology*; D002384:Catalysis; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity
C435691:MTMR9 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor