The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity

Adam Hage; Preeti Bharaj; Sarah van Tol; Maria I. Giraldo; Maria Gonzalez-Orozco; Karl M. Valerdi; Abbey N. Warren; Leopoldo Aguilera-Aguirre; Xuping Xie; Steven Widen; Hong M. Moulton; Benhur Lee; Jeffrey R. Johnson; Nevan J. Krogan; Adolfo García-Sastre; Pei-Yong Shi; Alexander N. Freiberg; Ricardo Rajsbaum Gorodezky

doi:10.1016/j.celrep.2022.110434

The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity

Adam Hage, Preeti Bharaj, Sarah van Tol, Maria I. Giraldo, Maria Gonzalez-Orozco, Karl M. Valerdi, Abbey N. Warren, Leopoldo Aguilera-Aguirre, Xuping Xie, Steven Widen, Hong M. Moulton, Benhur Lee, Jeffrey R. Johnson, Nevan J. Krogan, Adolfo García-Sastre, Pei-Yong Shi, Alexander N. Freiberg, Ricardo Rajsbaum Gorodezky

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

Type I interferons (IFN-I) are essential to establish antiviral innate immunity. Unanchored (or free) polyubiquitin (poly-Ub) has been shown to regulate IFN-I responses. However, few unanchored poly-Ub interactors are known. To identify factors regulated by unanchored poly-Ub in a physiological setting, we developed an approach to isolate unanchored poly-Ub from lung tissue. We identified the RNA helicase DHX16 as a potential pattern recognition receptor (PRR). Silencing of DHX16 in cells and in vivo diminished IFN-I responses against influenza virus. These effects extended to members of other virus families, including Zika and SARS-CoV-2. DHX16-dependent IFN-I production requires RIG-I and unanchored K48-poly-Ub synthesized by the E3-Ub ligase TRIM6. DHX16 recognizes a signal in influenza RNA segments that undergo splicing and requires its RNA helicase motif for direct, high-affinity interactions with specific viral RNAs. Our study establishes DHX16 as a PRR that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored poly-Ub.

Original language	English (US)
Article number	110434
Journal	Cell Reports
Volume	38
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2022.110434
State	Published - Mar 8 2022

Keywords

DHX16
RIG-I
SARS-CoV-2
TRIM6
influenza A virus
innate immunity
splicing
tripartite motif (TRIM) protein
type I interferon
unanchored ubiquitin

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110434

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Hage, A., Bharaj, P., van Tol, S., Giraldo, M. I., Gonzalez-Orozco, M., Valerdi, K. M., Warren, A. N., Aguilera-Aguirre, L., Xie, X., Widen, S., Moulton, H. M., Lee, B., Johnson, J. R., Krogan, N. J., García-Sastre, A., Shi, P.-Y., Freiberg, A. N., & Rajsbaum Gorodezky, R. (2022). The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity. Cell Reports, 38(10), Article 110434. https://doi.org/10.1016/j.celrep.2022.110434

Hage, A, Bharaj, P, van Tol, S, Giraldo, MI , Gonzalez-Orozco, M, Valerdi, KM, Warren, AN, Aguilera-Aguirre, L, Xie, X, Widen, S, Moulton, HM, Lee, B, Johnson, JR, Krogan, NJ, García-Sastre, A, Shi, P-Y, Freiberg, AN & Rajsbaum Gorodezky, R 2022, 'The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity', Cell Reports, vol. 38, no. 10, 110434. https://doi.org/10.1016/j.celrep.2022.110434

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title = "The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity",

abstract = "Type I interferons (IFN-I) are essential to establish antiviral innate immunity. Unanchored (or free) polyubiquitin (poly-Ub) has been shown to regulate IFN-I responses. However, few unanchored poly-Ub interactors are known. To identify factors regulated by unanchored poly-Ub in a physiological setting, we developed an approach to isolate unanchored poly-Ub from lung tissue. We identified the RNA helicase DHX16 as a potential pattern recognition receptor (PRR). Silencing of DHX16 in cells and in vivo diminished IFN-I responses against influenza virus. These effects extended to members of other virus families, including Zika and SARS-CoV-2. DHX16-dependent IFN-I production requires RIG-I and unanchored K48-poly-Ub synthesized by the E3-Ub ligase TRIM6. DHX16 recognizes a signal in influenza RNA segments that undergo splicing and requires its RNA helicase motif for direct, high-affinity interactions with specific viral RNAs. Our study establishes DHX16 as a PRR that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored poly-Ub.",

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AU - Hage, Adam

AU - Bharaj, Preeti

AU - van Tol, Sarah

AU - Giraldo, Maria I.

AU - Gonzalez-Orozco, Maria

AU - Valerdi, Karl M.

AU - Warren, Abbey N.

AU - Aguilera-Aguirre, Leopoldo

AU - Xie, Xuping

AU - Widen, Steven

AU - Moulton, Hong M.

AU - Lee, Benhur

AU - Johnson, Jeffrey R.

AU - Krogan, Nevan J.

AU - García-Sastre, Adolfo

AU - Shi, Pei-Yong

AU - Freiberg, Alexander N.

AU - Rajsbaum Gorodezky, Ricardo

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N2 - Type I interferons (IFN-I) are essential to establish antiviral innate immunity. Unanchored (or free) polyubiquitin (poly-Ub) has been shown to regulate IFN-I responses. However, few unanchored poly-Ub interactors are known. To identify factors regulated by unanchored poly-Ub in a physiological setting, we developed an approach to isolate unanchored poly-Ub from lung tissue. We identified the RNA helicase DHX16 as a potential pattern recognition receptor (PRR). Silencing of DHX16 in cells and in vivo diminished IFN-I responses against influenza virus. These effects extended to members of other virus families, including Zika and SARS-CoV-2. DHX16-dependent IFN-I production requires RIG-I and unanchored K48-poly-Ub synthesized by the E3-Ub ligase TRIM6. DHX16 recognizes a signal in influenza RNA segments that undergo splicing and requires its RNA helicase motif for direct, high-affinity interactions with specific viral RNAs. Our study establishes DHX16 as a PRR that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored poly-Ub.

AB - Type I interferons (IFN-I) are essential to establish antiviral innate immunity. Unanchored (or free) polyubiquitin (poly-Ub) has been shown to regulate IFN-I responses. However, few unanchored poly-Ub interactors are known. To identify factors regulated by unanchored poly-Ub in a physiological setting, we developed an approach to isolate unanchored poly-Ub from lung tissue. We identified the RNA helicase DHX16 as a potential pattern recognition receptor (PRR). Silencing of DHX16 in cells and in vivo diminished IFN-I responses against influenza virus. These effects extended to members of other virus families, including Zika and SARS-CoV-2. DHX16-dependent IFN-I production requires RIG-I and unanchored K48-poly-Ub synthesized by the E3-Ub ligase TRIM6. DHX16 recognizes a signal in influenza RNA segments that undergo splicing and requires its RNA helicase motif for direct, high-affinity interactions with specific viral RNAs. Our study establishes DHX16 as a PRR that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored poly-Ub.

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KW - SARS-CoV-2

KW - TRIM6

KW - influenza A virus

KW - innate immunity

KW - splicing

KW - tripartite motif (TRIM) protein

KW - type I interferon

KW - unanchored ubiquitin

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VL - 38

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 110434

ER -

The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity

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