title: Charcot-Marie-Tooth disease-linked protein SIMPLE functions with the ESCRT machinery in endosomal trafficking.
abstract: Mutations in small integral membrane protein of lysosome/late endosome (SIMPLE) cause autosomal dominant, Charcot-Marie-Tooth disease (CMT) type 1C. The cellular function of SIMPLE is unknown and the pathogenic mechanism of SIMPLE mutations remains elusive. Here, we report that SIMPLE interacted and colocalized with endosomal sorting complex required for transport (ESCRT) components STAM1, Hrs, and TSG101 on early endosomes and functioned with the ESCRT machinery in the control of endosome-to-lysosome trafficking. Our analyses revealed that SIMPLE was required for efficient recruitment of ESCRT components to endosomal membranes and for regulating endosomal trafficking and signaling attenuation of ErbB receptors. We found that the ability of SIMPLE to regulate ErbB trafficking and signaling was impaired by CMT-linked SIMPLE mutations via a loss-of-function, dominant-negative mechanism, resulting in prolonged activation of ERK1/2 signaling. Our findings indicate a function of SIMPLE as a regulator of endosomal trafficking and provide evidence linking dysregulated endosomal trafficking to CMT pathogenesis.
authors.affiliation: Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Lee
authors.forename: Lih-Shen
authors.initials: LS
authors.lastname: Chin
authors.forename: Lian
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001692:Biological Transport; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D012583:Schwann Cells; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; C118738:LITAF protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases