The orphan receptor IL-17RD is a negative regulator of RIG-I-like receptor-dependent antiviral innate immunity and restrains SARS-CoV-2-induced lung inflammation
- 1Universite de Montreal
Abstract
Detection of viral RNA by the RIG-I-like receptors (RLRs) RIG-I and MDA5 triggers assembly of a MAVS-dependent signalosome that activates the TBK1-IRF3 and IKK{beta}-NF-{kappa}B axes together with the JNK and p38 MAPK modules, driving type I and type III interferon (IFN) and inflammatory cytokine production. Because unrestrained activity of this pathway is a major cause of immunopathology, host-encoded negative regulators are essential, yet the full complement of these brakes remains incompletely defined. Here we identify interleukin-17 receptor D (IL-17RD, also known as SEF), an orphan member of the IL-17 receptor family previously characterized as an antagonist of FGF and Toll-like receptor signaling, as a negative regulator of RLR-driven antiviral innate immunity. Using a CRISPR-engineered and shRNA-depleted human airway epithelial-derived lung carcinoma A549 cell line, we show that loss of IL-17RD amplifies and prolongs phosphorylation of TBK1 and IRF3 in response to poly I:C transfection and to infection with encephalomyocarditis virus (EMCV) or Sendai virus (SeV), and likewise potentiates the IKK{beta}-I{kappa}B module and the TAK1-JNK1/2 and p38 MAPK branches. This translates into increased nuclear accumulation of IRF3 and p65, and markedly elevated induction of IFNB1, IFNL1-3, CCL5, IL6, and NFKBIA transcripts, as well as secreted IFN-{beta} and IL-6. Silencing IL-17RD in ACE2-expressing A549 cells similarly derepresses the antiviral and inflammatory transcriptional programme following SARS-CoV-2 infection. Epistasis experiments place IL-17RD at the level of MAVS, downstream of the RLR sentinels. Mechanistically, IL-17RD localizes to the ER-to-Golgi intermediate compartment (ERGIC), the membrane platform on which the MAVS signalosome is present, and associates with RIG-I, MDA5, MAVS, TBK1 and IRF3. Its re-expression in depleted cells redistributes RLR effectors and TRAF proteins across low-molecular-weight signalosome fractions, reducing the amount of IRF3 recruited to the 670 kDa MAVS signalosome complex. Complementation of IL-17RD-deficient cells also indicates that the intracellular TIR subdomain is sufficient to confer this antagonistic activity. Finally, Il17rd-/- mice display a splenic transcriptome enriched for antiviral response signatures, and, following intranasal infection with a moderate dose of SARS-CoV-2, they mount an exaggerated pulmonary cytokine response and develop significantly greater lung inflammation and fibrosis than wild-type littermates. Together, these data establish IL-17RD as a bona fide brake on the RLR-MAVS axis that limits virus-induced immunopathology, and identify the SEFIR/TIR subdomain as the module responsible for this activity.
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BibTeX
@misc{elmortada2026orphan,
title = {{The orphan receptor IL-17RD is a negative regulator of RIG-I-like receptor-dependent antiviral innate immunity and restrains SARS-CoV-2-induced lung inflammation}},
author = {F. El-Mortada and J. Roy and C. Girondel and F. Do and A. C. Dos Santos Pereira Andrade and E. Lacasse and I. Dubuc and P. P. Roux and G. St-Jean and B. Demey and N. Labrecque and L. Flamand and S. Meloche and M. J. Servant},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.747870},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.747870v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The orphan receptor IL-17RD is a negative regulator of RIG-I-like receptor-dependent antiviral innate immunity and restrains SARS-CoV-2-induced lung inflammation
AU - F. El-Mortada
AU - J. Roy
AU - C. Girondel
AU - F. Do
AU - A. C. Dos Santos Pereira Andrade
AU - E. Lacasse
AU - I. Dubuc
AU - P. P. Roux
AU - G. St-Jean
AU - B. Demey
AU - N. Labrecque
AU - L. Flamand
AU - S. Meloche
AU - M. J. Servant
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.747870
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.747870v1
AB - Detection of viral RNA by the RIG-I-like receptors (RLRs) RIG-I and MDA5 triggers assembly of a MAVS-dependent signalosome that activates the TBK1-IRF3 and IKK{beta}-NF-{kappa}B axes together with the JNK and p38 MAPK modules, driving type I and type III interferon (IFN) and inflammatory cytokine production. Because unrestrained activity of this pathway is a major cause of immunopathology, host-encoded negative regulators are essential, yet the full complement of these brakes remains incompletely defined. Here we identify interleukin-17 receptor D (IL-17RD, also known as SEF), an orphan member of the IL-17 receptor family previously characterized as an antagonist of FGF and Toll-like receptor signaling, as a negative regulator of RLR-driven antiviral innate immunity. Using a CRISPR-engineered and shRNA-depleted human airway epithelial-derived lung carcinoma A549 cell line, we show that loss of IL-17RD amplifies and prolongs phosphorylation of TBK1 and IRF3 in response to poly I:C transfection and to infection with encephalomyocarditis virus (EMCV) or Sendai virus (SeV), and likewise potentiates the IKK{beta}-I{kappa}B module and the TAK1-JNK1/2 and p38 MAPK branches. This translates into increased nuclear accumulation of IRF3 and p65, and markedly elevated induction of IFNB1, IFNL1-3, CCL5, IL6, and NFKBIA transcripts, as well as secreted IFN-{beta} and IL-6. Silencing IL-17RD in ACE2-expressing A549 cells similarly derepresses the antiviral and inflammatory transcriptional programme following SARS-CoV-2 infection. Epistasis experiments place IL-17RD at the level of MAVS, downstream of the RLR sentinels. Mechanistically, IL-17RD localizes to the ER-to-Golgi intermediate compartment (ERGIC), the membrane platform on which the MAVS signalosome is present, and associates with RIG-I, MDA5, MAVS, TBK1 and IRF3. Its re-expression in depleted cells redistributes RLR effectors and TRAF proteins across low-molecular-weight signalosome fractions, reducing the amount of IRF3 recruited to the 670 kDa MAVS signalosome complex. Complementation of IL-17RD-deficient cells also indicates that the intracellular TIR subdomain is sufficient to confer this antagonistic activity. Finally, Il17rd-/- mice display a splenic transcriptome enriched for antiviral response signatures, and, following intranasal infection with a moderate dose of SARS-CoV-2, they mount an exaggerated pulmonary cytokine response and develop significantly greater lung inflammation and fibrosis than wild-type littermates. Together, these data establish IL-17RD as a bona fide brake on the RLR-MAVS axis that limits virus-induced immunopathology, and identify the SEFIR/TIR subdomain as the module responsible for this activity.
ER -