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Vol. 15, Issue 1, 189-196, January 2004

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Disease-related Myotubularins Function in Endocytic Traffic in Caenorhabditis elegans

Hope Dang ^*, Zhai Li , Edward Y. Skolnik , and Hanna Fares ^* 

^* Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721; Departments of Pharmacology and Cell Biology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016

Submitted August 19, 2003; Revised September 14, 2003; Accepted September 24, 2003
Monitoring Editor: Howard Riezman

MTM1, MTMR2, and SBF2 belong to a family of proteins called the myotubularins. X-linked myotubular myopathy, a severe congenital disorder characterized by hypotonia and generalized muscle weakness in newborn males, is caused by mutations in MTM1 (Laporte et al., 1996). Charcot-Marie-Tooth types 4B1 and 4B2 are severe demyelinating neuropathies caused by mutations in MTMR2 (Bolino et al., 2000) and SBF2/MTMR13 (Senderek et al., 2003), respectively. Although several myotubularins are known to regulate phosphoinositide-phosphate levels in cells, little is known about the actual cellular process that is defective in patients with these diseases. Mutations in worm MTM-6 and MTM-9, myotubularins belonging to two subgroups, disorganize phosphoinositide 3-phosphate localization and block endocytosis in the coelomocytes of Caenorhabditis elegans. We demonstrate that MTM-6 and MTM-9 function as part of a complex to regulate an endocytic pathway that involves the Arf6 GTPase, and we define protein domains required for MTM-6 activity.

Abbreviations used: Arf6, adenosine diphosphate-ribosylation factor 6; GFRP, green fluorescent protein; mRFP1, monomeric red fluorescent protein; PI, phosphoinositide; PI(3)P, phosphoinositide 3-phosphate; RNAi, RNA-mediated interference; BSA-Rhod, bovine serum albumin conjugated to rhodamine.

Online version of this article contains supplementary material for some figures. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: fares{at}email.arizona.edu.

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