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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 Liu
Review

Abstract

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.

Keywords

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

Abbreviations

IAV

Influenza A viruses

PB2

Polymerase basic protein 2

PB1

Polymerase basic protein 1

PA

Polymerase acidic protein

HA

Hemagglutinin

NP

Nucleoprotein

NA

Neuraminidase

M

Matrix protein

NS

Non-structural protein

AIVs

Avian influenza viruses

GISAID

Global initiative on sharing avian influenza data

RdRP

RNA-dependent RNA polymerase RdRp complex

EIV

Equine influenza virus

CIV

Canine influenza virus

TR

Triple-reassortment

SIV

Swine influenza virus

MHC

Major histocompatibility complex

RIG-I

Retinoic acid-induced gene protein I

CPSF30

Cleavage and polyadenylation specificity factor 30

IPS-1

Interferon beta promoter stimulating factor 1

NLRP3

NOD-like receptor family pyrin domain containing 3

AP-MS

Affinity purification and mass spectrometryAP-MS

HBV

Hepatitis B virus

HCV

Hepatitis C virus

HSV-1

Herpes simplex virus 1

RSV

Respiratory syncytial virus

JEV

Japanese encephalitis virus

CCHFV

Crimean-congo hemorrhagic fever virus

HIV

Human immunodeficiency virus

HPAIV

Highly pathogenic avian influenza virus

LPAIV

Low pathogenic avian influenza virus

Notes

Acknowledgements

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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