Supplemental Material
Immunomodulatory non-structural proteins of influenza A viruses
CarolinKlemm, Yvonne Boergeling, Stephan Ludwig, Christina Ehrhardt
Institute of Virology Muenster (IVM), WestfaelischeWilhelms-University Muenster, D-48149 Muenster, Germany
Corresponding author: Ehrhardt, C. ()
Table S1. NS1 interaction partnersFactor / Function or process / Investigated virus subtype / Interacting domain of NS1 / Refs
ADAR1 / Proviral host factor
Promoted ADAR1 editing activity / A/Puerto Rico/8/34 (H1N1)
A/New Caledonia/2006 (H1N1) / RBD / [S1]
Akt / Increased Akt phosphorylation / A/Puerto Rico/8/34 (H1N1) / RBD / [S2]
AXIN2 / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
B23 / Nuclear retention of NS1 / A/Udorn/72 (H3N2)
A/Brevig Mission/1/18 (H1N1)
A/mallard/Netherlands/12/00 (H7N3) / RBD (aa R38, K41)
NoLS (K219,R220, R231, R232) / [S2]
BAX / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
BCL2L11 / Antiviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
BID / Antiviral host factor / A/New Caledonia/2006 (H1N1) / RBD / [S3]
BRAF / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
Cellular DNA / Inhibited synthesis of antiviral genes / A/WSN/33 (H1N1) / RBD (aa R38, K41) / [S4]
CPSF30 / Inhibited 3’end cleavage and polyadenylation of host pre-mRNAs / A/Udorn/72 (H3N2) / ED (aa E96, F103, M106, L144, 184-188) / [S2, S5, S6]
Crk(L) / Activated PI3K signalling / A/mallard/Netherlands/12/00 (H7N3)
A/Udorn/72 (H3N2)
A/WSN/33 (H1N1) / SHB / [S7]
A/Brevig Mission/1/18 (H1N1)
A/mallard/Netherlands/12/00 (H7N3) / SHB (aa P215) / [S2, S5]
Translocation from the cytoplasm to the nucleus / A/WSN/33 (H1N1)
A/mallard/Netherlands/12/00 (H7N3) / SHB / [S8]
DDX3 / Role in virus-induced stress granule formation / A/Puerto Rico/8/34 (H1N1)
A/Swine/SK/18789/02 (H1N1) / RBD (aa R38, K41) / [S9]
DDX21 / DDX21 binds PB1 to inhibit vRNA synthesis, counteracted by NS1 / A/Udorn/72 (H3N2)
A/WSN/33 (H1N1) / RBD (aa R37, R38, K41, R44) / [S10]
Dlg1 / Sequestration of Dlg1 / A/blue-winged teal/MN/993/1980 (H6N6) / PBM ESEV motif / [S2]
A/Turkey/Italy/977/99 (H7N1)
dsRNA / Inhibition of OAS / n.d. / RBD (aa R35, R38, S42, R46, T49) + oligomerization via ED (aa W187) / [S5, S10]
E1B-AP5 / Nuclear retention of host mRNAs / A/WSN/33 (H1N1) / N and C terminus / [S2, S5]
EDC3 / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
eIF4GI / Supported preferential translation of viral mRNAs / A/Victoria/3/75 (H3N2) / aa 1-113 / [S2, S5]
Fibrillarin / Nuclear retention of NS1 / A/Udorn/72 (H3N2)
A/mallard/Netherlands/12/00 (H7N3) / RBD (aa R38, K41)
NoLS (aa K219, R220, R231, R232) / [S2]
Gas8 / Unknown / A/Swine/Colorado/1/77 (H3N2) / Full-length / [S2]
GBP1 / Inhibition of GTPase activity / A/Puerto Rico/8/34 (H1N1)
A/Swine/Jiangsu/2/2006 (H3N2)
A/Swine/Gangxi/7/07 (H9N2) / aa 123-144 / [S2]
Herc5 / E3 ligase for ISG15 conjugation to NS1 / A/Udorn/72 (H3N2) / RBD (aa K20, K41) / [S11]
A/WSN/33 (H1N1)
A/Puerto Rico/8/34 (H1N1) / ED (aa K108, K110, K126, K217, K219) / [S12]
hnRNP A2/B1 / Suppressed NS vRNA, NS1 mRNA and NS1 protein levels / A/Puerto Rico/8/34 (H1N1) / n.d. / [S13]
hnRNPs C, K, U, ILF3, DDX1 / Role in splicing and nuclear export of pre-mRNA / A/Swine/SK/18789/02 (H1N1) / n.d. / [S14]
Hsp90 / Promoted apoptosis / A/chicken/Jilin/2003 (H5N1)
A/swine/Colorado/1/1977 (H3N2) / n.d. / [S2]
IKK / Inhibited expression of antiviral genes / A/WSN/33 (H1N1)
A/Bar-headed Goose/Qinghai/12/05 (H5N1) / ED / [S15]
IL10RA / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
Importin α / Nuclear import of NS1 / A/Udorn/72 (H3N2)
A/WSN/33 (H1N1) / RBD (aa R37, R38, K41)
ED (aa K219, R220, R231, R232A) / [S2, S5]
LARP1 / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
Lin7C / Mislocalization of Lin7C / A/blue-winged teal/MN/993/1980 (H6N6) / PBM ESEV motif / [S2]
MAGI-1, -2, -3 / Role in tight junctions / A/blue-winged teal/MN/993/1980 (H6N6)
A/Turkey/Italy/977/99 (H7N1) / PBM ESEV motif / [S2]
MAVS / Inhibition of antiviral response / A/Puerto Rico/8/34 (H1N1) / n.d. / [S2]
NF90 / Antagonized NS1 interaction with PKR / A/Shanghai/2/2013 (H7N9) / RBD (aa R35, R38, K41, R46 / [S16]
NLRC5 / NS1 suppressed interaction between NLRC5 and RIG-I / A/Puerto Rico/8/34 (H1N1) / n.d. / [S17]
NOLC1 / Potential role in cell cycle and growth / A/Goose/Guangdong/1/96 (H5N1) / ED (aa D120, R195) / [S2, S18]
NS1-BP / Inhibition of host pre-mRNA splicing / A/WSN/33 (H1N1) / n.d. / [S2, S5]
NS1-I / 17 β-oestradioldehydrogenaseprecursorprotein / A/WSN/33 (H1N1)
A/Berkeley/1/68 (H2N2)
A/Beijing/32/92 (H3N2)
A/duck/Alberta/76 (H12N5)
A/turkey/Oregon/71 (H7N5) / n.d. / [S2]
Nucleolin / Nuclear retention of NS1 / A/Udorn/72 (H3N2)
A/Brevig Mission/1/18 (H1N1) / RBD (aa R38, K41)
NoLS (aa K219, R220, R231, R232) / [S2, S5]
Nup98 / Nuclear retention of host mRNAs / A/WSN/33 (H1N1) / n.d. / [S5]
NXF1 / Nuclear retention of host mRNAs / A/WSN/33 (H1N1) / N and C terminus / [S2, S5]
Transport of viral mRNAs / A/Puerto Rico/8/34 (H1N1) / RBD and ED / [S19]
P15 / Nuclear retention of host mRNAs / A/WSN/33 (H1N1) / C terminus / [S2, S5]
P53 / Inhibition of apoptosis / A/Swine/Jiangsu/2/2006 (H3N2) / aa 144-188 + additional unknown regions / [S2]
P85 / Activation of PI3K signaling / A/Puerto Rico/8/34 (H1N1)
A/WSN/33 (H1N1)
A/Victoria/3/75 (H3N2) / aa Y89, M93
aa L141, E142
SHB (aa P164, P167) / [S5, S20]
Hyperactivation of PI3K / A/duck/Hunan/69/2004 (H5N1) / aa F138 / [S21]
PABII / Inhibition of the 3‘-end processing complex / A/Udorn/72 (H3N2) / ED (aa 223-237) / [S2, S5]
PABP1 / Promoted recruitment of 43S complexes to viral mRNAs / A/Victoria/3/75 (H3N2) / RBD (aa 1-81) / [S2, S5]
PACT / Inhibition of RIG-I activation / A/Puerto Rico/8/34 (H1N1)
A/laughing gull/Delaware bay/42/2006 (H7N3)
A/quail/California/D113023808/2012 (H4N2)
A/Perth/16/2006 (H3N2) / RBD / [S5, S22]
PAF1C / Inhibited synthesis of antiviral genes / H3N2 / Aa 226-229, ARSK motif / [S23]
PARP10 / Cell cycle arrest / H5N1 / n.d. / [S2]
PDZ domain / Binding of cellular host proteins / Avian strains / PDZ ligand motif / [S5]
PKR / Blocking of PKR activation / A/Udorn/72 (H3N2) / Aa 123-127 / [S2, S5]
PRP19 / Proviral host factor / A/Puerto Rico/8/34 (H1N1) / n.d. / [S24]
PTPL1 / Inhibited by NS1 to support Src activation / A/Turkey/Italy/977/99 (H7N1)
A/Hong Kong/213/03 (H5N1) / PBM (aa 225-230) / [S2]
Rae1 / Nuclear retention of host mRNAs / A/WSN/33 (H1N1) / N and C terminus / [S2, S5]
RAF1 / Proviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
RAP55 / Inhibited formation of stress granules and P-bodies / A/Vietnam/1194/2004 (H5N1)
A/WSN/33 (H1N1) / RBD (aa R38, K41)
ED (aa I123, M124, K126, N127) / [S2]
RIG-I / Inhibition of antiviral signaling / A/Brevig Mission/1918 (H1N1) / RBD (direct binding) / [S25]
A/Puerto Rico/8/34 (H1N1) / RBD (aa R38, K41, indirect binding) / [S5, S26]
RIL / Activation of Src signaling / A/Turkey/Italy/977/99 (H7N1)
A/Hong Kong/213/03 (H5N1) / PBM (aa 221-230) / [S2]
Riplet / Inhibition of antiviral signaling / A/Puerto Rico/8/34 (H1N1)
A/Swine/Texas/4199-2/98 (H3N2)
A/HongKong/156/1997 (H5N1)
A/California/04/09 (H1N1)
A/Texas/36/1991 (H1N1)
A/Panama/2007/1999 (H3N2) / RBD (aa R38, K41) / [S2, S27]
RHA / Proviral host factor / A/Puerto Rico/8/34 (H1N1)
A/Texas/36/91 (H1N1)
A/Halifax/210/2009 (H1N1) / RBD (aa R38, K41) / [S2]
Scribble / Inhibition of proapoptotic function / A/blue-winged teal/MN/993/1980 (H6N6) / PBM ESEV motif / [S2]
SF2 / Regulated splicing of NS1 and NEP mRNA / A/Zhejiang/DTID-ZJU01/2013 (H7N9) / RBD (aa R38, K41) / [S28]
Src / Stimulation of Src tyrosine kinase / A/Turkey/Italy/977/99 (H7N1) / SHB domain / [S2]
Staufen / Possible promotion of viral mRNA translation / A/Victoria/3/75 (H3N2) / C terminus / [S2, S5]
TAF1 / Antiviral host factor / A/New Caledonia/2006 (H1N1) / n.d. / [S3]
TRIM25 / Inhibition of antiviral signaling / A/Puerto Rico/8/34 (H1N1) / RBD (aa R38, K41) / [S29]
A/Texas/36/91 (H1N1)
A/New Caledonia/20/1999 (H1N1)
A/Wyoming/3/2003 (H3N2)
A/Panama/2007/1999 (H3N2)
A/Vietnam/1203/2004 (H5N1)
A/Hong Kong/156/97 (H5N1)
A/Swine/Texas/4199-2/98 (H3N2)
A/Brevig Mission/1918 (H1N1) / ED (aa E96, E97) / [S2]
β-tubulin / Induction of apoptosis / A/Beijing/501/2009 (H1N1) / RBD / [S2]
Ubc9 / E2 conjugating enzyme that conjugated SUMO1 to NS1 / A/Duck/Hubei/L-1/2004 (H5N1)
A/WSN/33 (H1N1) / C terminus (aa K219, K221) / [S30]
Viral mRNA / NS1 facilitated transport of late unspliced viral mRNA / A/Puerto Rico/8/34 (H1N1) / RBD (aa R38, K41, N81)
ED (aa S103, I106) / [S19]
Viral NP / Part of NS1-CPSF30 complex / A/WSN/33 (H1N1)
A/Hong Kong/156/97 (H5N1) / RBD / [S2]
Viral / Part of NS1-CPSF30 complex / A/Hong Kong/156/97 (H5N1) / n.d. / [S2]
polymerase / n.d. / A/Victoria/3/75 (H3N2) / n.d. / [S5]
A: alanine
aa: amino acid
ADAR1: adenosine deaminase acting on RNA 1
Akt: Protein kinase B, serine/threonine-specific protein kinase
AXIN2: axis inhibition protein 2
B23: nucleolar protein, ribosome assembly factor
BAX: B-cell lymphoma 2 –associated X protein
BCL2L11: B-cell lymphoma 2 –like protein 11
BID: BH3 interacting-domain death agonist
BRAF: rapidly accelerated fibrosarcoma isoform B
C: cysteine
CPSF30: 30kDa subunit of cleavage and polyadenylation specificity factor
Crk: Chicken tumor virus number 10 regulator of kinase
CrkL: Crk-like adaptor protein
DDX: DEAD-box helicase
Dlg1: discs large homolog 1
E: glutamic acid
E1B-AP5: Adenovirus early region 1B-associated protein 5
ED: Effector domain
EDC3: enhancer of mRNA decapping 3
eIF4GI: eukaryotic translation initiation factor 4 gamma 1
F: phenylalanine
Gas8: growth arrest specific 8
GBP1: guanylate-binding protein 1
Herc5: HECT and RLD domain containing E3 ubiquitin protein ligase 5
hnRNP: heterogeneous nuclear ribonucleoproteins
Hsp90: heat-shock protein 90
K: lysine
IKK: inhibitor of kappa B kinase
IL10RA: interleukin 10 receptor subunit alpha
ILF3: interleukin enhancer-binding factor 3
L: leucine
LARP1: La-related protein 1
Lin7C: protein lin-7 homolog C
M: methionine
MAGI: membrane associated guanylate kinase
MAVS: mitochondrial antiviral signalling protein
mRNA: messenger RNA
n.d.: not determined
NEP: nuclear export protein
NF90: nuclear factor 90
NLRC5: Nucleotide oligomerization domain –like receptor C5
NOLC1: nucleolar and coiled-body phosphoprotein 1
NoLS: nucleolar localization signal
NP: nucleoprotein
NS1: non-structural protein 1
NS1-BP: NS1-binding protein
NS1-I: NS1 interactor
Nup98: nucleoporin 98
NXF1: nuclear RNA export factor 1
OAS: 2-5-oligoadenylate synthetase
P: proline
p15: part of the nuclear export machinery for mRNA
p53: tumor suppressor 53
p85: regulatory subunit of PI3K
PABII: polyadenylate-bindingprotein 2
PABP1: polyadenylate-bindingprotein 1
PACT: protein activator of the interferon-induced protein kinase
PAF1C: RNA polymerase-associated factor 1 complex
PARP10: poly(ADP-ribose) polymerase 10
PBM: PDZ-ligand binding motif
PI3K: phosphatidylinositol-3-kinase
PKR: protein kinase R
PRP19: pre-mRNA-processing factor 19
PTPL1: protein tyrosine phosphatase L1
R: arginine
Rae1: ribonucleic acid export 1
RAF1: rapidly accelerated fibrosarcoma 1
RAP55: RNA-associated protein 55
RBD: RNA binding domain
RIG-I: retinoic acid inducible-gene I
RIL: reversion-induced LIM protein
RHA: RNA helicase A
S: serine
SF2: Serine/arginine-rich splicing factor
SHB: Src-homology type 3 binding motif
Src: sarcoma tyrosine kinase
SUMO: small ubiquitin-related modifier
T: threonine
TAF1: TATA-box binding protein associated factor 1
TRIM25: tripartite motif-containing protein 25
U: selenocysteine
Ubc9: ubiquitincarrierprotein 9
V: valine
vRNA: viral RNA
W: tryptophan
Y: tyrosine
Table S2. PB1-F2 interaction partnersFactor / Function or process / Investigated virus subtype / Interacting domain of PB1-F2 / Refs
ANT3 / Increased PB1-F2-induced apoptosis / A/Puerto Rico/8/34 (H1N1) / C terminus (aa 39-87) / [S31]
BAK, BAX / Essential for PB1-F2 induction of apoptosis / A/Puerto Rico/8/34 (H1N1) / n.d. / [S32]
CALCOCO2 / Inhibited IFN response and promoted NFkB activation / A/WSN/33 (H1N1) / C terminus / [S33]
Gβ2 / Unknown role in IAV infection / A/Puerto Rico/8/34 (H1N1) / n.d. / [S34]
IKK / Impaired NF-kB binding to DNA / A/Quail/Hong Kong/G1/97 (H9N2)
A/Puerto Rico/8/34 (H1N1)
A/turkey/England/50-92/91 (H5N1)
A/turkey/Turkey/1/2005 (H5N1) / Full-length / [S35]
IMM / Induced mitochondrial dysfunction and cell death / A/Puerto Rico/8/34 (H1N1) / MTS (aa 65-87) / [S32]
MAVS / Inhibition of antiviral signaling / A/Puerto Rico/8/34 (H1N1) / C terminus (S66) / [S36]
Membranes / Induction of cell cytotoxicity / A/WSN/33 (H1N1) / Full-length (aa 1-90) / [S37]
N (aa 1-52) and C (aa 53-90) terminus / [S38]
MIF / Unknown role in IAV infection / A/Puerto Rico/8/34 (H1N1) / n.d. / [S34]
NLRX1 / Neutralization of PB1-F2, prevented apoptosis and promoted IFN response / A/Puerto Rico/8/34 (H1N1) / n.d. / [S39]
PKC / Phosphorylation / A/Puerto Rico/8/34 (H1N1) / Aa T27, S35 / [S40]
Tom40 / Mitochondrial translocation / A/Puerto Rico/8/34 (H1N1) / Independent of MTS / [S41]
VDAC1 / Predisposed mitochondria to permeability transition / A/Puerto Rico/8/34 (H1N1) / N (aa 1-38) and C (aa39-87) terminus / [S31]
Viral PB1 / Increased viral polymerase activity / A/Puerto Rico/8/34 (H1N1) A/WSN/33 (H1N1) / N (aa 1-50) and C (aa 51-87) terminus / [S40]
aa: amino acid
ANT3: adenine nucleotide translocase 2
BAK: B-cell lymphoma 2 antagonist/killer 1
BAX: B-cell lymphoma 2 -associated X protein
CALCOCO2: calcium-binding and coiled-coil domain 2
Gβ2: G-protein β2 subunit
IAV: influenza A virus
IFN: interferon
IKK: inhibitor of kappa B kinase
IMM: inner mitochondrial membrane
MAVS: mitochondrial antiviral signalling protein
MIF: macrophage migration inhibitory factor
MTS: mitochondrial targeting sequence
n.d.: not determined
NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells
NLRX1: nucleotide-binding oligomerization domain, leucine rich repeat containing X1
PB1: polymerase basic protein 1
PKC: protein kinase C
S: serine
T: threonine
Tom40: translocase of the outer membrane 40
VDAC1: voltage-dependent anion-selective channel protein 1
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