title: Phosphoinositide regulation of integrin trafficking required for muscle attachment and maintenance.
abstract: Muscles must maintain cell compartmentalization when remodeled during development and use. How spatially restricted adhesions are regulated with muscle remodeling is largely unexplored. We show that the myotubularin (mtm) phosphoinositide phosphatase is required for integrin-mediated myofiber attachments in Drosophila melanogaster, and that mtm-depleted myofibers exhibit hallmarks of human XLMTM myopathy. Depletion of mtm leads to increased integrin turnover at the sarcolemma and an accumulation of integrin with PI(3)P on endosomal-related membrane inclusions, indicating a role for Mtm phosphatase activity in endocytic trafficking. The depletion of Class II, but not Class III, PI3-kinase rescued mtm-dependent defects, identifying an important pathway that regulates integrin recycling. Importantly, similar integrin localization defects found in human XLMTM myofibers signify conserved MTM1 function in muscle membrane trafficking. Our results indicate that regulation of distinct phosphoinositide pools plays a central role in maintaining cell compartmentalization and attachments during muscle remodeling, and they suggest involvement of Class II PI3-kinase in MTM-related disease.
authors.affiliation: Section of Cell and Developmental Biology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Inês
authors.initials: I
authors.lastname: Ribeiro
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.forename: Guy
authors.initials: G
authors.lastname: Tanentzapf
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
authors.forename: Amy
authors.initials: A
authors.lastname: Kiger
mesh_terms: D000818:Animals; D002451:Cell Compartmentation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement; D058541:Class II Phosphatidylinositol 3-Kinases / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics*; D024510:Muscle Development / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000235:genetics; D010716:Phosphatidylinositols / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D039001:Integrin alpha Chains; D010716:Phosphatidylinositols; C082188:if protein, Drosophila; D058541:Class II Phosphatidylinositol 3-Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin