Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy

ABSTRACT Avian influenza A viruses generally do not replicate efficiently in human cells, but substitution of glutamic acid (Glu, E) for lysine (Lys, K) at residue 627 of avian influenza virus polymerase basic protein 2 (PB2) can serve to overcome host restriction and facilitate human infectivity. A...

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Autores principales:	Shu-Ming Kuo, Chi-Jene Chen, Shih-Cheng Chang, Tzu-Jou Liu, Yi-Hsiang Chen, Sheng-Yu Huang, Shin-Ru Shih
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	PB2 TUFM autophagy host restriction factor influenza A virus mitochondria Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0898f53584e6442ab2ef417c827290f1
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spelling	oai:doaj.org-article:0898f53584e6442ab2ef417c827290f12021-11-15T15:51:29ZInhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy10.1128/mBio.00481-172150-7511https://doaj.org/article/0898f53584e6442ab2ef417c827290f12017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00481-17https://doaj.org/toc/2150-7511ABSTRACT Avian influenza A viruses generally do not replicate efficiently in human cells, but substitution of glutamic acid (Glu, E) for lysine (Lys, K) at residue 627 of avian influenza virus polymerase basic protein 2 (PB2) can serve to overcome host restriction and facilitate human infectivity. Although PB2 residue 627 is regarded as a species-specific signature of influenza A viruses, host restriction factors associated with PB2627E have yet to be fully investigated. We conducted immunoprecipitation, followed by differential proteomic analysis, to identify proteins associating with PB2627K (human signature) and PB2627E (avian signature) of influenza A/WSN/1933(H1N1) virus, and the results indicated that Tu elongation factor, mitochondrial (TUFM), had a higher binding affinity for PB2627E than PB2627K in transfected human cells. Stronger binding of TUFM to avian-signature PB2590G/591Q and PB2627E in the 2009 swine-origin pandemic H1N1 and 2013 avian-origin H7N9 influenza A viruses was similarly observed. Viruses carrying avian-signature PB2627E demonstrated increased replication in TUFM-deficient cells, but viral replication decreased in cells overexpressing TUFM. Interestingly, the presence of TUFM specifically inhibited the replication of PB2627E viruses, but not PB2627K viruses. In addition, enhanced levels of interaction between TUFM and PB2627E were noted in the mitochondrial fraction of infected cells. Furthermore, TUFM-dependent autophagy was reduced in TUFM-deficient cells infected with PB2627E virus; however, autophagy remained consistent in PB2627K virus-infected cells. The results suggest that TUFM acts as a host restriction factor that impedes avian-signature influenza A virus replication in human cells in a manner that correlates with autophagy. IMPORTANCE An understanding of the mechanisms that influenza A viruses utilize to shift host tropism and the identification of host restriction factors that can limit infection are both critical to the prevention and control of emerging viruses that cross species barriers to target new hosts. Using a proteomic approach, we revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells. We further found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans. These findings provide new insight regarding the TUFM mitochondrial protein and may have important implications for the development of novel antiviral strategies.Shu-Ming KuoChi-Jene ChenShih-Cheng ChangTzu-Jou LiuYi-Hsiang ChenSheng-Yu HuangShin-Ru ShihAmerican Society for MicrobiologyarticlePB2TUFMautophagyhost restriction factorinfluenza A virusmitochondriaMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	PB2 TUFM autophagy host restriction factor influenza A virus mitochondria Microbiology QR1-502
spellingShingle	PB2 TUFM autophagy host restriction factor influenza A virus mitochondria Microbiology QR1-502 Shu-Ming Kuo Chi-Jene Chen Shih-Cheng Chang Tzu-Jou Liu Yi-Hsiang Chen Sheng-Yu Huang Shin-Ru Shih Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
description	ABSTRACT Avian influenza A viruses generally do not replicate efficiently in human cells, but substitution of glutamic acid (Glu, E) for lysine (Lys, K) at residue 627 of avian influenza virus polymerase basic protein 2 (PB2) can serve to overcome host restriction and facilitate human infectivity. Although PB2 residue 627 is regarded as a species-specific signature of influenza A viruses, host restriction factors associated with PB2627E have yet to be fully investigated. We conducted immunoprecipitation, followed by differential proteomic analysis, to identify proteins associating with PB2627K (human signature) and PB2627E (avian signature) of influenza A/WSN/1933(H1N1) virus, and the results indicated that Tu elongation factor, mitochondrial (TUFM), had a higher binding affinity for PB2627E than PB2627K in transfected human cells. Stronger binding of TUFM to avian-signature PB2590G/591Q and PB2627E in the 2009 swine-origin pandemic H1N1 and 2013 avian-origin H7N9 influenza A viruses was similarly observed. Viruses carrying avian-signature PB2627E demonstrated increased replication in TUFM-deficient cells, but viral replication decreased in cells overexpressing TUFM. Interestingly, the presence of TUFM specifically inhibited the replication of PB2627E viruses, but not PB2627K viruses. In addition, enhanced levels of interaction between TUFM and PB2627E were noted in the mitochondrial fraction of infected cells. Furthermore, TUFM-dependent autophagy was reduced in TUFM-deficient cells infected with PB2627E virus; however, autophagy remained consistent in PB2627K virus-infected cells. The results suggest that TUFM acts as a host restriction factor that impedes avian-signature influenza A virus replication in human cells in a manner that correlates with autophagy. IMPORTANCE An understanding of the mechanisms that influenza A viruses utilize to shift host tropism and the identification of host restriction factors that can limit infection are both critical to the prevention and control of emerging viruses that cross species barriers to target new hosts. Using a proteomic approach, we revealed a novel role for TUFM as a host restriction factor that exerts an inhibitory effect on avian-signature PB2627E influenza virus propagation in human cells. We further found that increased TUFM-dependent autophagy correlates with the inhibitory effect on avian-signature influenza virus replication and may serve as a key intrinsic mechanism to restrict avian influenza virus infection in humans. These findings provide new insight regarding the TUFM mitochondrial protein and may have important implications for the development of novel antiviral strategies.
format	article
author	Shu-Ming Kuo Chi-Jene Chen Shih-Cheng Chang Tzu-Jou Liu Yi-Hsiang Chen Sheng-Yu Huang Shin-Ru Shih
author_facet	Shu-Ming Kuo Chi-Jene Chen Shih-Cheng Chang Tzu-Jou Liu Yi-Hsiang Chen Sheng-Yu Huang Shin-Ru Shih
author_sort	Shu-Ming Kuo
title	Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
title_short	Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
title_full	Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
title_fullStr	Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
title_full_unstemmed	Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy
title_sort	inhibition of avian influenza a virus replication in human cells by host restriction factor tufm is correlated with autophagy
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/0898f53584e6442ab2ef417c827290f1
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Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy

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