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Published online
doi:10.1083/jcb.200706034
The Journal of Cell Biology, Vol. 179, No. 5, 935-950
The Rockefeller University Press, 0021-9525 $30.00
© Kumar et al.
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Article

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



K.G. Suresh Kumar1,2, Hervé Barriere3,4, Christopher J. Carbone1,2, Jianghuai Liu1,2, Gayathri Swaminathan1,2, Ping Xu5, Ying Li1,2, Darren P. Baker6, Junmin Peng5, Gergely L. Lukacs3,4, and Serge Y. Fuchs1,2

1 Department of Animal Biology and 2 Mari Lowe Center for Comparative Oncology Research, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
3 Program in Cell and Lung Biology, Hospital for Sick Children Research Institute, Department of Laboratory Medicine and Pathobiology and 4 Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1X8, Canada
5 Department of Human Genetics, Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322
6 Biogen Idec, Inc., Cambridge, MA 02142

Correspondence to Serge Y. Fuchs: syfuchs{at}vet.upenn.edu

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}/β receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCFβTrcp (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.

K.G.S. Kumar and H. Barriere contributed equally to this paper.

Abbreviations used in this paper: AP, adaptin protein complex; βTrcp, β-transducin repeats–containing protein; EGFR, EGF receptor; FRIA, fluorescence ratio image analysis; HBS, Hepes-buffered saline; IFNAR1, IFN-{alpha}/β receptor 1; MESNA, 2-mercaptoethanesulfonic acid; SCF, Skp1–Cullin1–F-box complex; shRNA, short hairpin RNA.


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