Involvement of the Ubiquitin-Proteasome Pathway in the Degradation of Nontyrosine Kinase-Type Cytokine Receptors of IL-9, IL-2, and Erythropoietin

Abstract

The ubiquitin-dependent proteasome-mediated (Ub-Pr) degradation pathway has been shown to regulate a large variety of substrates, including nuclear, cytosolic, and membrane proteins. In mammalian systems, polyubiquitin modification has been identified in a number of cell surface receptors for more than a decade; however, its biological significance has remained unclear until recently. For growth factor receptors with intrinsic tyrosine kinase domains, polyubiquitination is believed to trigger the internalization and subsequent degradation via the lysosomal pathway. In this study we provide the first evidence that non-tyrosine kinase-type cytokine surface receptors, IL-9R α-chain, IL-2 receptor β-chain, and erythropoietin receptor, can be polyubiquitinated and degraded by proteasomes. The Ub-Pr pathway regulates both the basal level turnover and the ligand-induced degradation of the receptors. A previously identified putative molecular chaperon, valosin-containing protein, undergoes tyrosine phosphorylation in a cytokine-dependent manner and associates with the receptor complexes following receptor engagement, suggesting that valosin-containing protein may target the ubiquitinated receptors to the proteasome for degradation.

Role of the proteasome in modulating native G-CSFR expression

“…Several members of the Type I cytokine receptor family have been shown to undergo ligandinduced ubiquitination and internalization [17,[20][21][22][23][24][25]. Perhaps the best characterized of these is the GHR.…”

“…For the Type I cytokine receptors, endocytosis and degradation has been best characterized for the growth hormone receptor (GH-R), interleukin-2 receptor (IL-2R), and the erythropoietin receptor (EpoR) [20][21][22][23][24][25]. These receptors all undergo ligand-induced ubiquitination.…”

Plasma Membrane Receptor Complexes

“…CDC48A may be involved in targeting polyubiquitinated receptors for degradation in the proteasome, like it was shown for the mammalian cytokine receptors IL-2 and IL-9, the erythropoietin receptor, and the CDC48 homolog p97 (Yen et al, 2000). Another hypothesis is that the CDC48A protein mediates ERAD-like quality control of SERK1 receptors.…”

Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization

“…Since βc and ∆βc protein levels were not regulated by cytokine-induced transcriptional mechanisms, we next investigated whether ∆βc was generated by proteolysis of the βc cytoplasmic domain. The established role of proteasomes in degrading cytoplasmic proteins, as well as several mammalian plasma membrane receptors (21)(22)(23)(24)(25), led us to speculate that ∆βc might be generated by proteasomal degradation of the βc cytoplasmic domain. Indeed, pretreatment of cells with 50 µM of the proteasome inhibitor LLnL for 1 hour, followed by IL-5 stimulation, inhibited induction of ∆βc (Figure 2a, top panel, bottom arrow) and resulted in stable levels of full-length βc protein (Figure 2a, top panel, top arrow).…”