title: TRE17/USP6 regulates ubiquitylation and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis.
abstract: Plasma membrane proteins that enter cells by clathrin-independent endocytosis (CIE) are sorted either to lysosomes for degradation or recycled back to the plasma membrane. Expression of some MARCH E3 ubiquitin ligases promotes trafficking of CIE cargo proteins to lysosomes by ubiquitylating the proteins. Here, we show that co-expression of the ubiquitin-specific protease TRE17/USP6 counteracts the MARCH-dependent targeting of CIE cargo proteins, but not that of transferrin receptor, to lysosomes, leading to recovery of the stability and cell surface level of the proteins. The ubiquitylation of CIE cargo proteins by MARCH8 was reversed by TRE17, suggesting that TRE17 leads to deubiquitylation of CIE cargo proteins. The effects of TRE17 were dependent on its deubiquitylating activity and expression of TRE17 alone led to a stabilization of surface major histocompatibility complex class I (MHCI) molecules, a CIE cargo, suggesting that deubiquitylation of endogenous CIE cargo proteins promotes their stability. This study demonstrates that cycles of ubiquitylation and deubiquitylation can determine whether CIE cargo proteins are degraded or recycled.
authors.affiliation: Cell Biology & Physiology Center, NHLBI, NIH, Bethesda, MD 20891, USA Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Funakoshi
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Philadelphia, PA19104, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Chou
authors.affiliation: Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kanaho
authors.affiliation: Cell Biology & Physiology Center, NHLBI, NIH, Bethesda, MD 20891, USA donaldsonj@helix.nih.gov.
authors.forename: Julie G
authors.initials: JG
authors.lastname: Donaldson
mesh_terms: D002966:Clathrin / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002966:Clathrin; D011518:Proto-Oncogene Proteins; C473330:USP6 protein, human; D043222:Ubiquitin Thiolesterase
keywords: Cargo sorting; Lysosome; TRE17; USP6; Ubiquitin; Ubiquitin-specific protease