Citation: Ruiqi Sun, Yanyu Guo, Lilin Zhang, Huixia Zhang, Boxuan Yin, Xiaoyang Li, Changyan Li, Liu Yang, Lei Zhang, Zexing Li, Jinhai Huang. PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity .VIROLOGICA SINICA, 2024, 39(2) : 264-276.  http://dx.doi.org/10.1016/j.virs.2024.01.005

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity

  • Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

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    1. ABDOLI, A., ALIREZAEI, M., MEHRBOD, P. & FOROUZANFAR, F., 2018. Autophagy:The multi-purpose bridge in viral infections and host cells. Rev Med Virol. 28, e1973.

    2. ALBINA, E., CARRAT, C. & CHARLEY, B., 1998. Interferon-alpha response to swine arterivirus (PoAV), the porcine reproductive and respiratory syndrome virus. J Interferon Cytokine Res. 18, 485-490.

    3. AN, T. Q., LI, J. N., SU, C. M. & YOO, D., 2020. Molecular and Cellular Mechanisms for PRRSV Pathogenesis and Host Response to Infection. Virus Res. 286, 197980.

    4. AVIA, M., ROJAS, J. M., MIORIN, L., PASCUAL, E., VAN RIJN, P. A., MARTíN, V., GARCíA-SASTRE, A. & SEVILLA, N., 2019. Virus-induced autophagic degradation of STAT2 as a mechanism for interferon signaling blockade. EMBO Rep. 20, e48766.

    5. BEALE, R., WISE, H., STUART, A., RAVENHILL, B. J., DIGARD, P. & RANDOW, F., 2014. A LC3-interacting motif in the influenza A virus M2 protein is required to subvert autophagy and maintain virion stability. Cell Host Microbe. 15, 239-247.

    6. BOYLE, K. B. & RANDOW, F., 2013. The role of 'eat-me' signals and autophagy cargo receptors in innate immunity. Curr Opin Microbiol. 16, 339-348.

    7. CHEN, M., MENG, Q., QIN, Y., LIANG, P., TAN, P., HE, L., ZHOU, Y., CHEN, Y., HUANG, J., WANG, R. F. & CUI, J., 2016. TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses. Mol Cell. 64, 105-119.

    8. CHEN, Q., MEN, Y., WANG, D., XU, D., LIU, S., XIAO, S. & FANG, L., 2020. Porcine reproductive and respiratory syndrome virus infection induces endoplasmic reticulum stress, facilitates virus replication, and contributes to autophagy and apoptosis. Sci Rep. 10, 13131.

    9. CHIRAMEL, A. I., BRADY, N. R. & BARTENSCHLAGER, R., 2013. Divergent roles of autophagy in virus infection. Cells. 2, 83-104.

    10. CHOI, Y., BOWMAN, J. W. & JUNG, J. U., 2018. Autophagy during viral infection-a double-edged sword. Nat Rev Microbiol. 16, 341-354.

    11. DIAO, F., JIANG, C., SUN, Y., GAO, Y., BAI, J., NAUWYNCK, H., WANG, X., YANG, Y., JIANG, P. & LIU, X., 2023. Porcine reproductive and respiratory syndrome virus infection triggers autophagy via ER stress-induced calcium signaling to facilitate virus replication. PLoS Pathog. 19, e1011295.

    12. DING, W. X. & YIN, X. M., 2008. Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 4, 141-50.

    13. GU, H., ZHENG, S., HAN, G., YANG, H., DENG, Z., LIU, Z. & HE, F., 2022. Porcine Reproductive and Respiratory Syndrome Virus Adapts Antiviral Innate Immunity via Manipulating MALT1. mBio. 13, e0066422.

    14. GUAN, K., SU, Q., KUANG, K., MENG, X., ZHOU, X. & LIU, B., 2022. MiR-142-5p/FAM134B Axis Manipulates ER-Phagy to Control PRRSV Replication. Front Immunol. 13, 842077.

    15. HUANG, C., DU, Y., YU, Z., ZHANG, Q., LIU, Y., TANG, J., SHI, J. & FENG, W. H., 2016. Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Nsp4 Cleaves VISA to Impair Antiviral Responses Mediated by RIG-I-like Receptors. Sci Rep. 6, 28497.

    16. IWASAKI, A. & MEDZHITOV, R., 2015. Control of adaptive immunity by the innate immune system. Nat Immunol. 16, 343-353.

    17. JOUNAI, N., TAKESHITA, F., KOBIYAMA, K., SAWANO, A., MIYAWAKI, A., XIN, K. Q., ISHII, K. J., KAWAI, T., AKIRA, S., SUZUKI, K. & OKUDA, K., 2007. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A. 104, 14050-5.

    18. KEFFABER, K., 1989. Reproduction failure of unknown etiology. Am. Assoc. Swine Pract. Newsl. 1, 1-9.

    19. LI, R., CHEN, C., HE, J., ZHANG, L., ZHANG, L., GUO, Y., ZHANG, W., TAN, K. & HUANG, J., 2019. E3 ligase ASB8 promotes porcine reproductive and respiratory syndrome virus proliferation by stabilizing the viral Nsp1α protein and degrading host IKKβ kinase. Virology. 532, 55-68.

    20. LI, Y., HU, B., JI, G., ZHANG, Y., XU, C., LEI, J., DING, C. & ZHOU, J., 2020. Cytoplasmic Cargo Receptor p62 Inhibits Avibirnavirus Replication by Mediating Autophagic Degradation of Viral Protein VP2. J Virol. 94, e01255-20.

    21. LI, Y., XU, L., JIAO, D., ZHENG, Z., CHEN, Z., JING, Y., LI, Z., MA, Z., FENG, Y., GUO, X., WANG, Y., HE, Y., ZHENG, H. & XIAO, S., 2023. Genomic similarity and antibody-dependent enhancement of immune serum potentially affect the protective efficacy of commercial MLV vaccines against NADC30-like PRRSV. Virol Sin. 38, 813-826.

    22. LIANG, S., WU, Y. S., LI, D. Y., TANG, J. X. & LIU, H. F., 2021. Autophagy in Viral Infection and Pathogenesis. Front Cell Dev Biol. 9, 766142.

    23. LIPPAI, M. & LŐW, P., 2014. The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. Biomed Res Int. 2014, 832704.

    24. LUNNEY, J. K., FANG, Y., LADINIG, A., CHEN, N., LI, Y., ROWLAND, B. & RENUKARADHYA, G. J., 2016. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV):Pathogenesis and Interaction with the Immune System. Annu Rev Anim Biosci. 4, 129-54.

    25. LUO, R., XIAO, S., JIANG, Y., JIN, H., WANG, D., LIU, M., CHEN, H. & FANG, L., 2008. Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon-beta production by interfering with the RIG-I signaling pathway. Mol Immunol. 45, 2839-46.

    26. MA, X., LU, C., CHEN, Y., LI, S., MA, N., TAO, X., LI, Y., WANG, J., ZHOU, M., YAN, Y. B., LI, P., HEYDARI, K., DENG, H., ZHANG, M., YI, C. & GE, L., 2022. CCT2 is an aggrephagy receptor for clearance of solid protein aggregates. Cell. 185, 1325-1345.e22.

    27. MATSUMOTO, G., WADA, K., OKUNO, M., KUROSAWA, M. & NUKINA, N., 2011. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell. 44, 279-289.

    28. MONTANER-TARBES, S., DEL PORTILLO, H. A., MONTOYA, M. & FRAILE, L., 2019. Key Gaps in the Knowledge of the Porcine Respiratory Reproductive Syndrome Virus (PRRSV). Front Vet Sci. 6, 38.

    29. NAN, Y., WU, C., GU, G., SUN, W., ZHANG, Y. J. & ZHOU, E. M., 2017. Improved Vaccine against PRRSV:Current Progress and Future Perspective. Front Microbiol. 8, 1635.

    30. ONOMOTO, K., ONOGUCHI, K. & YONEYAMA, M., 2021. Regulation of RIG-I-like receptor-mediated signaling:interaction between host and viral factors. Cell Mol Immunol. 18, 539-555.

    31. PANKIV, S., CLAUSEN, T. H., LAMARK, T., BRECH, A., BRUUN, J. A., OUTZEN, H., ØVERVATN, A., BJøRKøY, G. & JOHANSEN, T., 2007. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 282, 24131-45.

    32. PILLI, M., ARKO-MENSAH, J., PONPUAK, M., ROBERTS, E., MASTER, S., MANDELL, M. A., DUPONT, N., ORNATOWSKI, W., JIANG, S., BRADFUTE, S. B., BRUUN, J. A., HANSEN, T. E., JOHANSEN, T. & DERETIC, V., 2012. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity. 37, 223-234.

    33. PRADEL, B., ROBERT-HEBMANN, V. & ESPERT, L., 2020. Regulation of Innate Immune Responses by Autophagy:A Goldmine for Viruses. Front Immunol. 11, 578038.

    34. REHWINKEL, J. & GACK, M. U., 2020. RIG-I-like receptors:their regulation and roles in RNA sensing. Nat Rev Immunol. 20, 537-551.

    35. SáNCHEZ-MARTíN, P. & KOMATSU, M., 2018. p62/SQSTM1-steering the cell through health and disease. J Cell Sci. 131, jcs222836.

    36. SHI, P., SU, Y., LI, R., ZHANG, L., CHEN, C., ZHANG, L., FAABERG, K. & HUANG, J., 2018. Dual Regulation of Host TRAIP Post-translation and Nuclear/Plasma Distribution by Porcine Reproductive and Respiratory Syndrome Virus Non-structural Protein 1α Promotes Viral Proliferation. Front Immunol. 9, 3023.

    37. SUN, R., GUO, Y., LI, X., LI, R., SHI, J., TAN, Z., ZHANG, L., ZHANG, L., HAN, J. & HUANG, J., 2022. PRRSV Non-Structural Proteins Orchestrate Porcine E3 Ubiquitin Ligase RNF122 to Promote PRRSV Proliferation. Viruses. 14, 424.

    38. SUN, Y., HAN, M., KIM, C., CALVERT, J. G. & YOO, D., 2012. Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus. Viruses. 4, 424-446.

    39. SUN, Y., KE, H., HAN, M., CHEN, N., FANG, W. & YOO, D., 2016. Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Suppresses Both MAVS and RIG-I Expression as One of the Mechanisms to Antagonize Type I Interferon Production. PLoS One. 11, e0168314.

    40. TAN, J. M., WONG, E. S., KIRKPATRICK, D. S., PLETNIKOVA, O., KO, H. S., TAY, S. P., HO, M. W., TRONCOSO, J., GYGI, S. P., LEE, M. K., DAWSON, V. L., DAWSON, T. M. & LIM, K. L., 2008. Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum Mol Genet. 17, 431-439.

    41. VIRET, C., DUCLAUX-LORAS, R., NANCEY, S., ROZIèRES, A. & FAURE, M., 2021. Selective Autophagy Receptors in Antiviral Defense. Trends Microbiol. 29, 798-810.

    42. VU, H. L. X., PATTNAIK, A. K. & OSORIO, F. A., 2017. Strategies to broaden the cross-protective efficacy of vaccines against porcine reproductive and respiratory syndrome virus. Vet Microbiol. 206, 29-34.

    43. WANG, R. & ZHANG, Y. J., 2014. Antagonizing interferon-mediated immune response by porcine reproductive and respiratory syndrome virus. Biomed Res Int. 2014, 315470.

    44. WANG, R., ZHU, Y., REN, C., YANG, S., TIAN, S., CHEN, H., JIN, M. & ZHOU, H., 2021a. Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. Autophagy. 17, 496-511.

    45. WANG, T. Y., SUN, M. X., ZHANG, H. L., WANG, G., ZHAN, G., TIAN, Z. J., CAI, X. H., SU, C. & TANG, Y. D., 2021b. Evasion of Antiviral Innate Immunity by Porcine Reproductive and Respiratory Syndrome Virus. Front Microbiol. 12, 693799.

    46. WANG, Z., CHEN, J., WU, X., MA, D., ZHANG, X., LI, R., HAN, C., LIU, H., YIN, X., DU, Q., TONG, D. & HUANG, Y., 2021c. PCV2 targets cGAS to inhibit type I interferon induction to promote other DNA virus infection. PLoS Pathog. 17, e1009940.

    47. ZHANG, Z. & KLIONSKY, D. J., 2022. CCT2, a newly identified aggrephagy receptor in mammals, specifically mediates the autophagic clearance of solid protein aggregates. Autophagy. 18, 1483-1485.

    48. ZHOU, L., WANG, Z., DING, Y., GE, X., GUO, X. & YANG, H., 2015. NADC30-like Strain of Porcine Reproductive and Respiratory Syndrome Virus, China. Emerg Infect Dis. 21, 2256-2257.

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    PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity

    Abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

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