Autophagy: Identification of MTMR5 as a neuron-enriched suppressor

Abstract

A puzzle of autophagy in neurons is that, unlike in other cells, it is not robustly induced by inhibition of mammalian target of rapamycin (mTOR). A new study now solves this conundrum and establishes that myotubularin-related phosphatase 5 limits the induction of neuronal autophagy by mTOR inhibitors.

Figure 1.. Autophagy regulation by MTMR5 and MTMR2 in iNeurons and other cell types.

(A) In iNeurons differentiated from iPSCs, MTMR5 and MTMR2 antagonize the formation of autophagosomes, thereby desensitizing iNeurons to mTOR inhibition. This suppression is a result of the formation of MTMR5–MTMR2 heterodimers that reduce PI3P levels, thereby preventing the assembly of autophagy-initiating factors (top panel). Reduction of MTMR5 expression allows for autophagy induction and enhanced clearance of cargoes such as TDP-43 (bottom panel). (B) Cell-type-specific stoichiometries between factors that inhibit and promote autophagy may account for the differential regulation of autophagy in response to mTOR inhibition in iNeurons compared with iPSCs, iAstrocytes and iMuscle cells. iNeurons do not upregulate autophagy in response to mTOR inhibition and have higher levels of MTMR5–MTMR2 and lower levels of autophagy-promoting factors compared with the other cell types examined. By contrast, iPSCs, iAstrocytes, and iMuscle cells induce autophagy in response to mTOR inhibition and this effect may be due to varying proportions of lower levels of autophagy-inhibitory factors relative to higher levels of autophagy-promoting factors. ND, not determined.