Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of Type I interferon receptor

Sabyasachi Bhattacharya, Wei Chun HuangFu, Jianghuai Liu, Sudhakar Veeranki, Darren P. Baker, Constantinos Koumenis, J. Alan Diehl, Serge Y. Fuchs

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36 Citations (Scopus)


Phosphorylation-dependent ubiquitination and ensuing down-regulation and lysosomal degradation of the interferon α/β receptor chain 1 (IFNAR1) of the receptor for Type I interferons play important roles in limiting the cellular responses to these cytokines. These events could be stimulated either by the ligands (in a Janus kinase-dependent manner) or by unfolded protein response (UPR) inducers including viral infection (in a manner dependent on the activity of pancreatic endoplasmic reticulum kinase). Both ligand-dependent and -independent pathways converge on phosphorylation of Ser535 within the IFNAR1 degron leading to recruitment of β-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation. Casein kinase 1α (CK1α) was shown to directly phosphorylate Ser535 within the ligand-independent pathway. Yet given the constitutive activity of CK1α, it remained unclear how this pathway is stimulated by UPR. Here we report that induction of UPR promotes the phosphorylation of a proximal residue, Ser 532, in a pancreatic endoplasmic reticulum kinase-dependent manner. This serine serves as a priming site that promotes subsequent phosphorylation of IFNAR1 within its degron by CK1α. These events play an important role in regulating ubiquitination and degradation of IFNAR1 as well as the extent of Type I interferon signaling.

Original languageEnglish
Pages (from-to)2318-2325
Number of pages8
JournalJournal of Biological Chemistry
Issue number4
Publication statusPublished - Jan 22 2010
Externally publishedYes


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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