A novel SUMOylation site in the influenza a virus NS1 protein identified with a highly sensitive FRET assay

Way, George; Xiong, Zhehao; Wang, Guojun; Dai, Hanchu; Zheng, Shasha; García‐Sastre, Adolfo; Liao, Jiayu

doi:10.1016/j.jbiotec.2020.08.009

Cited by 9 publications

(14 citation statements)

References 31 publications

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“…In previous genome-wide siRNA or CRISPR screenings, SUMOylation enzymes were found to contribute to the IAV life cycle; moreover, many IAV proteins are SUMOylated [26,27,29]. We also recently identified important SUMOylation sites of IAV NS1, whose mutation significantly slows down the IAV growth [33]. More significantly, we recently discovered that IAV could be completely inhibited by a SUMOylation-specific inhibitor, STE025, which inhibited the E1 enzyme of SUMOylation and was discovered through a high-throughput screening campaign, and a critical SUMOylation site of IAV M1 protein was identified throughout the FRET-MS approach (Way et al, submitted).…”

Section: Ibv Is Completely Inhibited By the Sumoylation Specific Inhi...mentioning

confidence: 90%

“…Furthermore, many viral proteins are directly SUMOylated, such as the NS1, M1, NP, PA, and PB proteins of influenza viruses, and mutations of their SUMOylation sites have a significant impact on virus growth [26][27][28][29][30][31][32]. We recently identified critical or essential SUMOylation sites on IAV NS1 and M1 proteins, respectively, and these mutations either significantly reduce viral replication or completely abolish the virus growth [33] (Way, G., Submitted).…”

Section: Introductionmentioning

confidence: 99%

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Human SUMOylation Pathway Is Critical for Influenza B Virus

Dang

Rodgers

García‐Sastre

et al. 2022

Viruses

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The identification and elucidation of host pathways for viral infection are critical for understanding the viral infection processes and novel therapeutics development. Here, for the first time, we discover that the human SUMOylation pathway is essential for the IBV viral life cycle. First, IBV viruses were completely inhibited by a novel SUMOylation specific inhibitor, STE025, discovered from our FRET-based high-throughput screening, and the inhibition was very potent, with IC50~ 0.1 µM in an IBV-induced cell death rescue assay; Second, we determined that the IBV M1 protein was SUMOylated, which was mediated by the SUMOylation E2 conjugation enzyme and the E3 ligase enzyme at very high affinities, of 0.20 µM and 0.22 µM, respectively; Third, the mutation of the IBV M1 SUMOylation site, K21R, completely abolished the viral particle generation, strongly suggesting the requirement of SUMOylation for the IBV life cycle. These results suggest that the blockage of the host human SUMOylation pathway is very effective for IBV inhibition. We therefore propose that the host SUMOylation pathway is a critical host factor for the IBV virus life cycle. The identification and inhibition of critical host factor(s) provide a novel strategy for future anti-viral therapeutics development, such as IBV and other viruses.

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Section: Ibv Is Completely Inhibited By the Sumoylation Specific Inhi...mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Human SUMOylation Pathway Is Critical for Influenza B Virus

Dang

Rodgers

García‐Sastre

et al. 2022

Viruses

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“…SUMOylation can also modulate the subcellular localization of substrate proteins. For example, the influenza A virus nucleoprotein is essential for the intracellular trafficking of nucleoproteins and for viral growth [43,44]. The SUMOylation of Zika virus and Dengue virus NS5 proteins directs their nuclear localization [45].…”

Section: Discussionmentioning

confidence: 99%

SUMOylation Regulates BmNPV Replication by Moderating PKIP Intracellular Localization

Shen

Lü²,

Chen

et al. 2022

Processes

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SUMOylation is a reversible covalent process between a small ubiquitin-like modifier (SUMO) and its target protein and has become a crucial regulator of protein functions. Here, we report that Bombyx mori nucleopolyhedrovirus (BmNPV) may take advantage of the host SUMOylation system to enhance its own replication, similar to many other viruses. Both the knockdown of BmSUMO by RNAi and chemical blocking by ginkgolic acid both impaired BmNPV replication. Using site mutation and pull-down assays, we found that lysine K70 of the protein kinase-interacting protein (PKIP), which is conserved in all Alphabaculoviruses, was modified by SUMO. Mutation of K70 in PKIP led to its translocation from the cytoplasm to the nucleus. Knockout and rescue experiments showed that the rescue of PKIP mutant virus with wild-type PKIP restored BmNPV replication to the normal level, but this was not true for the K70R mutation. Altogether, these results show that SUMOylation of PKIP plays a key role in BmNPV replication.

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“…Indeed, some studies suggest that most of IAV strains possess a SUMOylated NS1 protein, and that different lysine residues can be targeted, even though K131 seems to be the main NS1 SUMOylation site. These studies also highlight the crucial, but not essential, role of NS1 SUMOylation in virus replication [339][340][341]. Santos et al notably showed that SUMOylation at K70 and K219 has no impact on NS1 stability and localization but can affect NS1 oligomerization and therefore NS1 functions.…”

Section: Sumoylation Systemmentioning

confidence: 93%

How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity

Lamotte

Tafforeau

2021

Viruses

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Ubiquitination is a post-translational modification regulating critical cellular processes such as protein degradation, trafficking and signaling pathways, including activation of the innate immune response. Therefore, viruses, and particularly influenza A virus (IAV), have evolved different mechanisms to counteract this system to perform proper infection. Among IAV proteins, the non-structural protein NS1 is shown to be one of the main virulence factors involved in these viral hijackings. NS1 is notably able to inhibit the host’s antiviral response through the perturbation of ubiquitination in different ways, as discussed in this review.

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A novel SUMOylation site in the influenza a virus NS1 protein identified with a highly sensitive FRET assay

Cited by 9 publications

References 31 publications

Human SUMOylation Pathway Is Critical for Influenza B Virus

Human SUMOylation Pathway Is Critical for Influenza B Virus

SUMOylation Regulates BmNPV Replication by Moderating PKIP Intracellular Localization

How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity

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