Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response.
Hantavirus nucleocapsid protein (NP) inhibits protein kinase R (PKR) dimerization by an unknown mechanism to counteract its antiviral responses during virus infection. Here we demonstrate that NP exploits an endogenous PKR inhibitor P58IPK to inhibit PKR. The activity of P58IPK is normally restricte...
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2021
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oai:doaj.org-article:fc347b4fe5674dde86684e65fbe767f42021-12-02T20:00:01ZHantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response.1553-73661553-737410.1371/journal.ppat.1010007https://doaj.org/article/fc347b4fe5674dde86684e65fbe767f42021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1010007https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Hantavirus nucleocapsid protein (NP) inhibits protein kinase R (PKR) dimerization by an unknown mechanism to counteract its antiviral responses during virus infection. Here we demonstrate that NP exploits an endogenous PKR inhibitor P58IPK to inhibit PKR. The activity of P58IPK is normally restricted in cells by the formation of an inactive complex with its negative regulator Hsp40. On the other hand, PKR remains associated with the 40S ribosomal subunit, a unique strategic location that facilitates its free access to the downstream target eIF2α. Although both NP and Hsp40 bind to P58IPK, the binding affinity of NP is much stronger compared to Hsp40. P58IPK harbors an NP binding site, spanning to N-terminal TPR subdomains I and II. The Hsp40 binding site on P58IPK was mapped to the TPR subdomain II. The high affinity binding of NP to P58IPK and the overlap between NP and Hsp40 binding sites releases the P58IPK from its negative regulator by competitive inhibition. The NP-P58IPK complex is selectively recruited to the 40S ribosomal subunit by direct interaction between NP and the ribosomal protein S19 (RPS19), a structural component of the 40S ribosomal subunit. NP has distinct binding sites for P58IPK and RPS19, enabling it to serve as bridge between P58IPK and the 40S ribosomal subunit. NP mutants deficient in binding to either P58IPK or RPS19 fail to inhibit PKR, demonstrating that selective engagement of P58IPK to the 40S ribosomal subunit is required for PKR inhibition. Cells deficient in P58IPK mount a rapid PKR antiviral response and establish an antiviral state, observed by global translational shutdown and rapid decline in viral load. These studies reveal a novel viral strategy in which NP releases P58IPK from its negative regulator and selectively engages it on the 40S ribosomal subunit to promptly combat the PKR antiviral responses.Zekun WangSongyang RenQiming LiAustin D RoysterLei LinSichen LiuSafder S GanaieJianming QiuSheema MirMohammad A MirPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 10, p e1010007 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Zekun Wang Songyang Ren Qiming Li Austin D Royster Lei Lin Sichen Liu Safder S Ganaie Jianming Qiu Sheema Mir Mohammad A Mir Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response. |
| description |
Hantavirus nucleocapsid protein (NP) inhibits protein kinase R (PKR) dimerization by an unknown mechanism to counteract its antiviral responses during virus infection. Here we demonstrate that NP exploits an endogenous PKR inhibitor P58IPK to inhibit PKR. The activity of P58IPK is normally restricted in cells by the formation of an inactive complex with its negative regulator Hsp40. On the other hand, PKR remains associated with the 40S ribosomal subunit, a unique strategic location that facilitates its free access to the downstream target eIF2α. Although both NP and Hsp40 bind to P58IPK, the binding affinity of NP is much stronger compared to Hsp40. P58IPK harbors an NP binding site, spanning to N-terminal TPR subdomains I and II. The Hsp40 binding site on P58IPK was mapped to the TPR subdomain II. The high affinity binding of NP to P58IPK and the overlap between NP and Hsp40 binding sites releases the P58IPK from its negative regulator by competitive inhibition. The NP-P58IPK complex is selectively recruited to the 40S ribosomal subunit by direct interaction between NP and the ribosomal protein S19 (RPS19), a structural component of the 40S ribosomal subunit. NP has distinct binding sites for P58IPK and RPS19, enabling it to serve as bridge between P58IPK and the 40S ribosomal subunit. NP mutants deficient in binding to either P58IPK or RPS19 fail to inhibit PKR, demonstrating that selective engagement of P58IPK to the 40S ribosomal subunit is required for PKR inhibition. Cells deficient in P58IPK mount a rapid PKR antiviral response and establish an antiviral state, observed by global translational shutdown and rapid decline in viral load. These studies reveal a novel viral strategy in which NP releases P58IPK from its negative regulator and selectively engages it on the 40S ribosomal subunit to promptly combat the PKR antiviral responses. |
| format |
article |
| author |
Zekun Wang Songyang Ren Qiming Li Austin D Royster Lei Lin Sichen Liu Safder S Ganaie Jianming Qiu Sheema Mir Mohammad A Mir |
| author_facet |
Zekun Wang Songyang Ren Qiming Li Austin D Royster Lei Lin Sichen Liu Safder S Ganaie Jianming Qiu Sheema Mir Mohammad A Mir |
| author_sort |
Zekun Wang |
| title |
Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response. |
| title_short |
Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response. |
| title_full |
Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response. |
| title_fullStr |
Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response. |
| title_full_unstemmed |
Hantaviruses use the endogenous host factor P58IPK to combat the PKR antiviral response. |
| title_sort |
hantaviruses use the endogenous host factor p58ipk to combat the pkr antiviral response. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/fc347b4fe5674dde86684e65fbe767f4 |
| work_keys_str_mv |
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