MTMR4, a phosphoinositide‐specific 3’‐phosphatase, regulates TFEB activity and the endocytic and autophagic pathways

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2018-08, Vol.23 (8), p.670-687
• Main Authors: Pham, Hoa Q., Yoshioka, Kazuaki, Mohri, Hiromi, Nakata, Hiroki, Aki, Sho, Ishimaru, Kazuhiro, Takuwa, Noriko, Takuwa, Yoh
• Format: Article
• Language: English
• Subjects: Alveoli; Amino acids; autophagosome; Autophagy; endosome; Endosomes; Epithelium; Kinases; lysosome; Lysosomes; membrane traffic; MTMR4; Nuclear transport; Organelles; Phagosomes; Phosphatase; phosphatidylinositol 3‐phosphate; TFEB
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/gtc.12609

Phosphatidylinositol 3‐phosphate (PI(3)P) is the predominant phosphoinositide species in early endosomes and autophagosomes, in which PI(3)P dictates traffic of these organelles. Phosphoinositide levels are tightly regulated by lipid‐kinases and ‐phosphatases; however, a phosphatase that converts PI(3)P back to phosphatidylinositol in the endosomal and autophagosomal compartments is not fully understood. We investigated the subcellular distribution and functions of myotubularin‐related protein‐4 (MTMR4), which is distinct among other MTMRs in that it possesses a PI(3)P‐binding FYVE domain, in lung alveolar epithelium‐derived A549 cells. MTMR4 was localized mainly in late endosomes and autophagosomes. MTMR4 knockdown markedly suppressed the motility, fusion, and fission of PI(3)P‐enriched structures, resulting in decreases in late endosomes, autophagosomes, and lysosomes, and enlargement of PI(3)P‐enriched early and late endosomes. In amino acid‐ and serum‐starved cells, MTMR4 knockdown decreased both autophagosomes and autolysosomes and markedly increased PI(3)P‐containing autophagosomes and late endosomes, suggesting that the fusion with lysosomes of autophagosomes and late endosomes might be impaired. Notably, MTMR4 knockdown inhibited the nuclear translocation of starvation stress responsive transcription factor‐EB (TFEB) with reduced expression of lysosome‐related genes in starved cells. These findings indicate that MTMR4 is essential for the integrity of endocytic and autophagic pathways. MTMR4, which is localized mainly in LEs and APs and regulates PI(3)P levels in these organelles, controls the fusion, fission, motility and maturation of endosomes, the autophagic pathway, and lysosomal biogenesis. MTMR4 is also required for activation of TFEB. This action of MTMR4 could contribute to MTMR4 regulation of the endocytic and autophagic pathways.