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Dev Cell. 2015 May 4;33(3):328-42. doi: 10.1016/j.devcel.2015.03.007.

A family of tetraspans organizes cargo for sorting into multivesicular bodies.

Author information

1
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
2
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
3
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Radiology and Biomedical Imaging, University of California San Francisco School of Medicine, San Francisco, CA 94143, USA.
4
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: katzmann.david@mayo.edu.
5
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA. Electronic address: robert-piper@uiowa.edu.

Abstract

The abundance of cell-surface membrane proteins is regulated by internalization and delivery into intralumenal vesicles (ILVs) of multivesicular bodies (MVBs). Many cargoes are ubiquitinated, allowing access to an ESCRT-dependent pathway into MVBs. Yet how nonubiquitinated proteins, such as glycosylphosphatidylinositol-anchored proteins, enter MVBs is unclear, supporting the possibility of mechanistically distinct ILV biogenesis pathways. Here we show that a family of highly ubiquitinated tetraspan Cos proteins provides a Ub signal in trans, allowing sorting of nonubiquitinated MVB cargo into the canonical ESCRT- and Ub-dependent pathway. Cos proteins create discrete endosomal subdomains that concentrate Ub cargo prior to their envelopment into ILVs, and the activity of Cos proteins is required not only for efficient sorting of canonical Ub cargo but also for sorting nonubiquitinated cargo into MVBs. Expression of these proteins increases during nutrient stress through an NAD(+)/Sir2-dependent mechanism that in turn accelerates the downregulation of a broad range of cell-surface proteins.

PMID:
25942624
PMCID:
PMC4421094
DOI:
10.1016/j.devcel.2015.03.007
[Indexed for MEDLINE]
Free PMC Article

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