Interleukin-1 Receptor, Sliced for Action

Science Signaling  20 Jan 2009:
Vol. 2, Issue 54, pp. ec21
DOI: 10.1126/scisignal.254ec21

Presenilin (PS1) is a component of the γ-secretase complex that mediates regulated intramembrane proteolysis. Such proteolyis of receptors in the cell membrane can have multiple effects on receptor function by releasing biologically active intracellular and extracellular domains. Such events can influence cytokine binding outside the cell or carry signals into the cell and into the nucleus. Elzinga et al. report a role for γ-secretase–dependent regulation of the interleukin-1 receptor type 1 (IL-1R1). IL-1R1 signals through association with a large complex of proteins that includes the ubiquitin ligase TRAF6 (tumor necrosis factor receptor–associated factor-6) and the protein pseudokinase IRAK 2 (interleukin-1 receptor–associated kinase 2). Elzinga et al. noted that PS1 has a consensus binding site for interaction with TRAF6 and showed by coimmunoprecipitation that endogenous PS1 and TRAF6 interacted in human embryonic kidney 293T cells. Furthermore, the interaction was enhanced when cells were treated with IL-1β. In transfected cells, PS1 also interacted with IRAK2. IL-1R1 was cleaved into a C-terminal fragment and an intracellular domain in a manner dependent on metalloprotease and γ-secretase activities. Ligand binding to IL-1R1 enhanced generation of the intracellular domain, and pharmacological inhibition of γ-secretase inhibited such cleavage and also inhibited biological responses to IL-1β. Thus, intramembrane proteolysis appears to be important for signaling through IL-1R1 (as it also appears to be for IL-1R2 and tumor necrosis factor–α). The authors note that such proteolysis could release the ectodomain of the receptor to compete for IL-1 binding. Cleavage could disrupt further signaling, but on the other hand, generation of the soluble intracellular domain could also allow movement of the ICD—which contains nuclear localization signals—to the nucleus to influence gene expression. The precise role of interactions between PS1 and TRAF6 and IRAK2 remains to be explained.

B. M. Elzinga, C. Twomey, J. C. Powell, F. Harte, J. V. McCarthy, Interleukin-1 receptor type 1 is a substrate for γ-secretase–dependent regulated intramembrane proteolysis. J. Biol. Chem. 284, 1394–1409 (2009). [Abstract] [Full Text]