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PMID: 18056411 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Site-specific ubiquitination exposes a linear motif to promote interferon-alpha receptor endocytosis.

The Journal of cell biology ·Vol. 179 ·No. 5 ·2007-12-03 ·Pages 935-50

Kumar KG, Barriere H, Carbone CJ, Liu J, Swaminathan G, Xu P, Li Y, Baker DP, Peng J, Lukacs GL, Fuchs SY

Abstract

Ligand-induced endocytosis and lysosomal degradation of cognate receptors regulate the extent of cell signaling. Along with linear endocytic motifs that recruit the adaptin protein complex 2 (AP2)-clathrin molecules, monoubiquitination of receptors has emerged as a major endocytic signal. By investigating ubiquitin-dependent lysosomal degradation of the interferon (IFN)-alpha/beta receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCF(betaTrcp) (Skp1-Cullin1-F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro. Although either polyubiquitin linkage suffices for postinternalization sorting, both types of chains are necessary but not sufficient for robust IFNAR1 turnover and internalization. These processes also depend on the proximity of ubiquitin-acceptor lysines to a linear endocytic motif and on its integrity. Furthermore, ubiquitination of IFNAR1 promotes its interaction with the AP2 adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process.

MeSH Terms
Amino Acid Motifs Cell Line Endocytosis Humans Lysine/metabolism Lysosomes/metabolism Phosphorylation Polyubiquitin/metabolism Protein Binding Protein Processing, Post-Translational Protein Transport Receptor, Interferon alpha-beta/chemistry,metabolism SKP Cullin F-Box Protein Ligases/metabolism Ubiquitination beta-Transducin Repeat-Containing Proteins/metabolism
Chemicals
beta-Transducin Repeat-Containing Proteins Polyubiquitin Receptor, Interferon alpha-beta SKP Cullin F-Box Protein Ligases Lysine
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kumar K G Suresh
Department of Animal Biology and 2Mari Lowe Center for Comparative Oncology Research, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Barriere Hervé
Carbone Christopher J
Liu Jianghuai
Swaminathan Gayathri
Xu Ping
Li Ying
Baker Darren P
Peng Junmin
Lukacs Gergely L
Fuchs Serge Y
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200706034
Published
2007-12-03
Pages
935-50
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2099190
Subset
IM
Grants
NIA NIH HHS · P50 AG025688 · United States
NCI NIH HHS · R01 CA092900 · United States
NCI NIH HHS · CA092900 · United States
NIA NIH HHS · AG025688 · United States
External Links
PubMed source DOI: 10.1083/jcb.200706034 PMC Full Text View journal details
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