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bioRxiv · 10.1101/318840

Regulation of IRAK1 Ubiquitination by the Antiviral Radical SAM Enzyme Viperin

Dumbrepatil, A. B.·Ghosh, S.·Patel, A. M.·Malec, P. A.·Zegalia, K.·Hoff, J. D.·Kennedy, R. T.·Marsh, E. N. G.
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Abstract

Viperin is a radical S-adenosylmethionine (SAM) enzyme that plays a multifaceted role in the cellular antiviral response. Viperin was recently shown to catalyze the SAM-dependent formation of 3'-deoxy-3',4'-didehydro-CTP (ddhCTP), which inhibits some viral RNA polymerases. Viperin is also implicated in regulating K63-linked poly-ubiquitination of interleukin-1 receptor-associated kinase-1 (IRAK1) by the E3 ubiquitin ligase TNF Receptor-Associated Factor 6 (TRAF6) as part of the Toll-like receptor-7 and 9 (TLR7/9) innate immune signaling pathways. We show that IRAK1 and TRAF6 activate viperin to efficiently catalyze the radical-mediated dehydration of CTP to ddhCTP. Furthermore, poly-ubiquitination of IRAK1 requires the association of viperin with IRAK1 and TRAF6. Poly-ubiquitination appears dependent on structural changes induced by SAM binding to viperin but does not require catalytically active viperin. The synergistic activation of viperin and IRAK1 provides a mechanism that couples innate immune signaling with the production of the antiviral nucleotide ddhCTP.

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Dumbrepatil, A. B., Ghosh, S., Patel, A. M., Malec, P. A., Zegalia, K., Hoff, J. D., Kennedy, R. T., Marsh, E. N. G.. 2018-05-21. Regulation of IRAK1 Ubiquitination by the Antiviral Radical SAM Enzyme Viperin. https://doi.org/10.1101/318840

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