The role of myotubularin-related phosphatases in the control of autophagy and programmed cell death

Abstract

We have investigated a previously little-studied subfamily of related active MTM proteins namely MTMR6, MTMR7, and MTMR8. All three of these proteins partner with the same inactive MTMR9 thus potentially creating competition. We find that complex formation in each case greatly stabilizes all of the proteins. In the absence of complex formation all of the proteins are markedly unstable. We examined the substrate specificity of the proteins and found that the MTMR8/MTMR9 complex prefers PtdIns(3)P as substrate while the MTMR6/MTMR9 complex prefers PtdIns(3,5)P2. In view of this difference the two complexes serve different functions in cells. The MTMR8/MTMR9 complex serves to inhibit autophagy while the MTMR6/MTMR9 complex inhibits apoptosis. We have also created a mouse heterozygous for Mtmr9 that displays a very strong phenotype with small size, ataxia, seizures, unrestrained growth of the teeth, and in most animals premature death. The heterozygous mice express markedly reduced levels of all of these MTM proteins presumably reflecting the instability of the monomeric proteins. This instability results in levels of the proteins that are much less than that expected in heterozygous animals.