A family of tetraspans organizes cargo for sorting into multivesicular bodies.
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.
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
Chris
C
MacDonald
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Johanna A
JA
Payne
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.
Mariam
M
Aboian
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
William
W
Smith
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: katzmann.david@mayo.edu.
David J
DJ
Katzmann
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA. Electronic address: robert-piper@uiowa.edu.
Robert C
RC
Piper
D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D057146:Multivesicular Bodies / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D025801:Ubiquitin