期刊
JOURNAL OF CELL SCIENCE
卷 119, 期 22, 页码 4689-4701出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.03249
关键词
endosome; Hrs; GRIF1; trafficking; kinesin; lysosome
类别
资金
- NIA NIH HHS [AG021489] Funding Source: Medline
- NINDS NIH HHS [NS047575] Funding Source: Medline
Endosomal sorting of internalized cell surface receptors to the lysosomal pathway plays a crucial role in the control of cell signaling and function. Here we report the identification of GABA(A) receptor interacting factor-1 (GRIF1),a recently discovered protein of unknown function, as a new regulator of endosome-to-lysosome trafficking. Yeast two-hybrid screen and co-immunoprecipitation analysis reveal that GRIF1 interacts with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), an essential component of the endosomal sorting machinery. We have mapped the binding domains of GRIF1 and Hrs that mediate their association and shown the colocalization of GRIF1 with Hrs on early endosomes. Like Hrs, both overexpression and siRNA-mediated depletion of GRIF1 inhibit the degradation of internalized epidermal growth factor receptors and block the trafficking of the receptors from early endosomes to the lysosomal pathway. Our results indicate, for the first time, a functional role for GRIF1 in the regulation of endosomal trafficking. Interestingly, overexpression of full-length GRIF1, but not the Hrs- or kinesin-interacting GRIF1 deletion mutants, causes a perinuclear clustering of early endosomes. Our findings suggest that GRIF1 may also participate in microtubule-based transport of early endosomes by acting as an adaptor linking Hrs- containing endosomes to kinesin.
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