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Originally published as MBC in Press, 10.1091/mbc.E09-06-0535 on October 28, 2009

Vol. 20, Issue 24, 5181-5194, December 15, 2009

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MICAL-L1 Links EHD1 to Tubular Recycling Endosomes and Regulates Receptor Recycling

Mahak Sharma, Sai Srinivas Panapakkam Giridharan, Juliati Rahajeng, Naava Naslavsky, and Steve Caplan

Department of Biochemistry and Molecular Biology and Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870

Submitted June 30, 2009; Revised October 8, 2009; Accepted October 19, 2009
Monitoring Editor: Sandra L. Schmid

Endocytic recycling of receptors and lipids occurs via a complex network of tubular and vesicular membranes. EHD1 is a key regulator of endocytosis and associates with tubular membranes to facilitate recycling. Although EHD proteins tubulate membranes in vitro, EHD1 primarily associates with preexisting tubules in vivo. How EHD1 is recruited to these tubular endosomes remains unclear. We have determined that the Rab8-interacting protein, MICAL-L1, associates with EHD1, with both proteins colocalizing to long tubular membranes, in vitro and in live cells. MICAL-L1 is a largely uncharacterized member of the MICAL-family of proteins that uniquely contains two asparagine-proline-phenylalanine motifs, sequences that typically interact with EH-domains. Our data show that the MICAL-L1 C-terminal coiled-coil region is necessary and sufficient for its localization to tubular membranes. Moreover, we provide unexpected evidence that endogenous MICAL-L1 can link both EHD1 and Rab8a to these structures, as its depletion leads to loss of the EHD1-Rab8a interaction and the absence of both of these proteins from the membrane tubules. Finally, we demonstrate that MICAL-L1 is essential for efficient endocytic recycling. These data implicate MICAL-L1 as an unusual type of Rab effector that regulates endocytic recycling by recruiting and linking EHD1 and Rab8a on membrane tubules.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09-06-0535) on October 28, 2009.

Address correspondence to: Steve Caplan (scaplan{at}unmc.edu) or Naava Naslavsky (nnaslavsky{at}unmc.edu).




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