Molecular mimicry between IL‐33 and KSHV for attachment to chromatin through the H2A–H2B acidic pocket

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Abstract
Interleukin‐33 (IL‐33) is an IL‐1‐like ligand for the ST2 receptor that stimulates the production of Th2‐associated cytokines. Recently, we showed that IL‐33 is a chromatin‐associated factor in the nucleus of endothelial cells in vivo. Here, we report the identification of a short IL‐33 chromatin‐binding peptide that shares striking similarities with a motif found in Kaposi sarcoma herpesvirus LANA (latency‐associated nuclear antigen), which is responsible for the attachment of viral genomes to mitotic chromosomes. Similar to LANA, the IL‐33 peptide docks into the acidic pocket formed by the H2A–H2B dimer at the nucleosomal surface and regulates chromatin compaction by promoting nucleosome–nucleosome interactions. Taken together, our data provide important new insights into the nuclear roles of IL‐33, and show a unique example of molecular mimicry of a chromatin‐associated cytokine by a DNA tumour virus. In addition, the data provide, to the best of our knowledge, the first demonstration of the existence of non‐histone cellular factors that bind to the acidic pocket of the nucleosome.