N-Terminal Domain of Nuclear IL-1α Shows Structural Similarity to the C-Terminal Domain of Snf1 and Binds to the HAT/Core Module of the SAGA Complex

Abstract

Interleukin-1α (IL-1α) is a proinflammatory cytokine and a key player in host immune responses in higher eukaryotes. IL-1α has pleiotropic effects on a wide range of cell types, and it has been extensively studied for its ability to contribute to various autoimmune and inflammation-linked disorders, including rheumatoid arthritis, Alzheimer’s disease, systemic sclerosis and cardiovascular disorders. Interestingly, a significant proportion of IL-1α is translocated to the cell nucleus, in which it interacts with histone acetyltransferase complexes. Despite the importance of IL-1α, little is known regarding its binding targets and functions in the nucleus. We took advantage of the histone acetyltransferase (HAT) complexes being evolutionarily conserved from yeast to humans and the yeast SAGA complex serving as an epitome of the eukaryotic HAT complexes. Using gene knock-out technique and co-immunoprecipitation of the IL-1α precursor with TAP-tagged subunits of the yeast HAT complexes, we mapped the IL-1α-binding site to the HAT/Core module of the SAGA complex. We also predicted the 3-D structure of the IL-1α N-terminal domain, and by employing structure similarity searches, we found a similar structure in the C-terminal regulatory region of the catalytic subunit of the AMP-activated/Snf1 protein kinases, which interact with HAT complexes both in mammals and yeast, respectively. This finding is further supported with the ability of the IL-1α precursor to partially rescue growth defects of snf1Δ yeast strains on media containing 3-Amino-1,2,4-triazole (3-AT), a competitive inhibitor of His3. Finally, the careful evaluation of our data together with other published data in the field allows us to hypothesize a new function for the ADA complex in SAGA complex assembly.

Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice

“…IL-1α belongs to the unique group of dual-function cytokines that can translocate into the nucleus via a nuclear localization sequence. [36] It was reported to bind to transcription activators [37,38], and facilitate inflammatory gene transcription upon its intracellular expression, independent of IL-1R1…”

HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins

“…126 In the nucleus, pIL-1α (but not mature IL-1α) also interacts with histone acetyltransferases and thus acts as a transcriptional regulator. 123, 127 In addition, upon stimulation with LPS or TNFα, pIL-1α translocates to the nucleus, where it was shown to promote the expression of inflammatory genes such as IL-6 and IL-8. 125, 128 In accordance with these findings, in systemic sclerosis fibroblasts, pIL-1α translocation was shown to depend on binding to HS1-associated protein X-1 (HAX-1) and induce the expression of IL-6 and pro-collagen (Figure 2).…”

Interleukin 1α and the inflammatory process

“…Nuclear localization of pro-IL-1α and IL-1α-NTP is functionally important, as they are able to interact directly with histone acetyltransferases p300, PCAF and GCN5 (refs. 46,47) and stimulate transcription of genes, including those encoding proinflammatory chemokines, independently of IL-1R1 signaling 48,49 . Furthermore, pro-IL-1α can bind chromatin 50 , and IL-1α-NTP localization to spliceosomes triggers apoptosis of numerous malignant cell types but not primary nontransformed cells 51 .…”