Medical Microbiology and Immunology

, Volume 207, Issue 5–6, pp 255–269 | Cite as

PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

  • Jiao Hu
  • Chunxi Ma
  • Xiufan LiuEmail author


PA-X, a fusion protein belonging to influenza A viruses (IAVs), integrating the N-terminal 191 amino acids of PA gene and the ribosomal frame-shifting product that lengthens out to 41 or 61 amino acids. Since its discovery in 2012, multiple functions have been attributed to this small protein, including a process, where wide-spread protein synthesis in infected host cells is shut down (called host shutoff), and viral replication, polymerase activity, viral-induced cell apoptosis, PA nuclear localization, and virulence are modulated. However, many of its proposed functions may be specific to strain, subtype, host, or cell line. In this review, we start by describing the well-defined global host-shutoff ability of PA-X and the potential mechanisms underlying it. We move on to the role played by PA-X in modulating innate and acquired immune responses in the host. We then systematically discuss the role played by PA-X in modulating the virulence of influenza viruses of different subtypes and host origins, and finish with a general overview of the research advances made in identifying the host cell partners that interact with PA-X. To uncover possible clues about the differential effects of PA-X in modulating viral virulence, we focus on systemically evaluating polymorphisms in PA-X from various viral subtypes and hosts, including avian and human H5N1, H5N6, H9N2, and H7N9 viruses. Finally, we conclude with a proposition regarding the possible future research directions for this important protein.


Influenza virus PA-X Host shutoff Immunomodulatory proteins Pathogenesis Virus–host interaction 



Influenza A viruses


Polymerase basic protein 2


Polymerase basic protein 1


Polymerase acidic protein








Matrix protein


Non-structural protein


Avian influenza viruses


Global initiative on sharing avian influenza data


RNA-dependent RNA polymerase RdRp complex


Equine influenza virus


Canine influenza virus




Swine influenza virus


Major histocompatibility complex


Retinoic acid-induced gene protein I


Cleavage and polyadenylation specificity factor 30


Interferon beta promoter stimulating factor 1


NOD-like receptor family pyrin domain containing 3


Affinity purification and mass spectrometryAP-MS


Hepatitis B virus


Hepatitis C virus


Herpes simplex virus 1


Respiratory syncytial virus


Japanese encephalitis virus


Crimean-congo hemorrhagic fever virus


Human immunodeficiency virus


Highly pathogenic avian influenza virus


Low pathogenic avian influenza virus



This work was supported by the National Natural Science Foundation of China (31502076), by the Jiangsu Provincial Natural Science Foundation of China (BK20150444), by the Special Financial Grant from the China Postdoctoral Science Foundation (2016T90515), by the National Key Research and Development Project of China (2016YFD0500202-1 and 2016YFD0501601), by the Earmarked Fund For China Agriculture Research System (CARS-40) by the “Qing Lan Project” of Higher Education Institutions of Jiangsu Province, China, by the “High-end talent support program” of Yangzhou University, China, and by A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author contributions

JH and LX drafted and revised the manuscript; CM contributed to the polymorphism analysis of the PA-X protein. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Animal Infectious Disease Laboratory, School of Veterinary MedicineYangzhou UniversityYangzhouChina
  2. 2.Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and ZoonosisYangzhou UniversityYangzhouChina
  3. 3.Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agri-food Safety and Quality, Ministry of Agriculture of China (26116120)Yangzhou UniversityYangzhouChina

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