Figure 1.
Molecular modifications of IL-1α that regulate its intracellular distribution and bioavailability. Constitutive or inducible expression of IL-1α produces full-length pro-IL-1α. After synthesis, pro-IL-1α is localized into the nucleus, cytosol or lysosomal compartment or is displayed on the outer leaflet of the plasma membrane. Intracellular localization of pro-IL-1α can change in response to specific stimuli and pro-IL-1α can also be cleaved by calpain to generate IL-1α-NTP and a mature C-terminal IL-1α form. Both IL-1α-NTP and pro-IL-1α possess a functional NLS signal and bind HAX1 to allow translocation into the nucleus. In the nucleus, IL-1α-NTP binds transcription regulation factors and activates expression of proinflammatory cytokines and chemokines independently of IL-1R1 signaling. Pro-IL-1α can bind chromatin, which allows sequestration of pro-IL-1α from the cytosol into the nucleus, thereby limiting aberrant IL-1α-dependent inflammation during apoptosis. In the cytosol, glycosylation of pro-IL-1α may allow pro-IL-1α translocation onto the outer surface of the cell. Plasma-membrane-bound pro-IL-1α can be released by mannose, suggesting a lectin-like mechanism of anchorage of pro-IL-1α to the outer leaflet of the plasma membrane. In the cytosol, pro-IL-1α can form a complex with inhibitory IL-1R2. Cytosolic pro-IL-1α can be polyubiquitinated, leading to its proteosomal degradation. Although several post-translational modifications of IL-1α-NTP and pro-IL-1α have been reported, formal confirmation of their functional importance is currently lacking.