SARS-CoV-2 ORF6 protein targets TRIM25 for proteasomal degradation to diminish K63-linked RIG-I ubiquitination and type-I interferon induction

Khatun, O and Sharma, M and Narayan, R and Tripathi, S (2023) SARS-CoV-2 ORF6 protein targets TRIM25 for proteasomal degradation to diminish K63-linked RIG-I ubiquitination and type-I interferon induction. In: Cellular and Molecular Life Sciences, 80 (12).

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Abstract

Evasion and antagonism of host cellular immunity upon SARS-CoV-2 infection provide replication advantage to the virus and contribute to COVID-19 pathogenesis. We explored the ability of different SARS-CoV-2 proteins to antagonize the host�s innate immune system and found that the ORF6 protein mitigated type-I Interferon (IFN) induction and downstream IFN signaling. Our findings also corroborated previous reports that ORF6 blocks the nuclear import of IRF3 and STAT1 to inhibit IFN induction and signaling. Here we show that ORF6 directly interacts with RIG-I and blocks downstream type-I IFN induction and signaling by reducing the levels of K63-linked ubiquitinated RIG-I. This involves ORF6-mediated targeting of E3 ligase TRIM25 for proteasomal degradation, which was also observed during SARS-CoV-2 infection. The type-I IFN antagonistic activity of ORF6 was mapped to its C-terminal cytoplasmic tail, specifically to amino acid residues 52�61. Overall, we provide new insights into how SARS-CoV-2 inhibits type-I IFN induction and signaling through distinct actions of the viral ORF6 protein. © 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Item Type:	Journal Article
Publication:	Cellular and Molecular Life Sciences
Publisher:	Springer Science and Business Media Deutschland GmbH
Additional Information:	The copyright for this article belongs to Springer Science and Business Media Deutschland GmbH.
Department/Centre:	Division of Biological Sciences > Centre for Infectious Disease Research
Date Deposited:	28 Feb 2024 11:42
Last Modified:	28 Feb 2024 11:42
URI:	https://eprints.iisc.ac.in/id/eprint/83631

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