Ligand-independent pathway that controls stability of interferon alpha receptor.
Ligand-specific negative regulation of cytokine-induced signaling relies on down regulation of the cytokine receptors. Down regulation of the IFNAR1 sub-unit of the Type I interferon (IFN) receptor proceeds via lysosomal receptor proteolysis, which is triggered by ubiquitination that depends on IFNAR1 serine phosphorylation. While IFN-inducible phosphorylation, ubiquitination, and degradation requires the catalytic activity of the Tyk2 Janus kinase, here we found the ligand- and Tyk2-independent pathway that promotes IFNAR1 phosphorylation, ubiquitination, and degradation when IFNAR1 is expressed at high levels. A major cellular kinase activity that is responsible for IFNAR1 phosphorylation in vitro does not depend on either ligand or Tyk2 activity. Inhibition of ligand-independent IFNAR1 degradation suppresses cell proliferation. We discuss the signaling events that might lead to ubiquitination and degradation of IFNAR1 via ligand-dependent and independent pathways and their potential physiologic significance.
Liu
Jianghuai
J
Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, School of Veterinary Medicine, University of Pennsylvania, Room 316 Hill Pavilion, 380 S University Avenue, Philadelphia, PA 19104-4539, USA.
Plotnikov
Alexander
A
Banerjee
Anamika
A
Suresh Kumar
K G
KG
Ragimbeau
Josiane
J
Marijanovic
Zrinka
Z
Baker
Darren P
DP
Pellegrini
Sandra
S
Fuchs
Serge Y
SY
D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008024:Ligands; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*
C507964:IFNAR1 protein, human; D008024:Ligands; D025801:Ubiquitin; D053633:Receptor, Interferon alpha-beta