Viral subversion of nucleocytoplasmic trafficking - PubMed (original) (raw)

Review

Viral subversion of nucleocytoplasmic trafficking

Melanie L Yarbrough et al. Traffic. 2014 Feb.

Abstract

Trafficking of proteins and RNA into and out of the nucleus occurs through the nuclear pore complex (NPC). Because of its critical function in many cellular processes, the NPC and transport factors are common targets of several viruses that disrupt key constituents of the machinery to facilitate viral replication. Many viruses such as poliovirus and severe acute respiratory syndrome (SARS) virus inhibit protein import into the nucleus, whereas viruses such as influenza A virus target and disrupt host mRNA nuclear export. Current evidence indicates that these viruses may employ such strategies to avert the host immune response. Conversely, many viruses co-opt nucleocytoplasmic trafficking to facilitate transport of viral RNAs. As viral proteins interact with key regulators of the host nuclear transport machinery, viruses have served as invaluable tools of discovery that led to the identification of novel constituents of nuclear transport pathways. This review explores the importance of nucleocytoplasmic trafficking to viral pathogenesis as these studies revealed new antiviral therapeutic strategies and exposed previously unknown cellular mechanisms. Further understanding of nuclear transport pathways will determine whether such therapeutics will be useful treatments for important human pathogens.

Keywords: mRNA export; nuclear import; nuclear pore complex; nuclear transport; nucleocytoplasmic trafficking; virus.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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Figures

Figure 1

Figure 1

Viral strategies to disrupt nucleocytoplasmic trafficking of proteins. Nuclear import pathways mediated by Kapα/Kapβ1 or Kapβ2 are shown. Kapα and Kapβ2 bind proteins or cargos with specific

NLS

s. Kapβ1 and β2 translocate the import complexes through the

NPC

via interactions with Nups. The import complexes are dissociated by

RanGTP

at the nucleoplasmic side of the

NPC

. Viral proteins (blue starbursts) interact with the depicted host factors to disrupt nuclear transport pathways.

2Apro

and

3Cpro

of

HRV

and

PV

degrade Nups and block nuclear import of proteins via the Kapα/β1 and Kapβ2 pathways.

SARS‐CoV ORF6

protein effectively disrupts nuclear import of phosphorylated

STAT1

by tethering

PY‐STAT1

–Kapα/Kapβ complex to

ER

/Golgi membranes. Alternatively,

EBOV‐VP24

binds Kapα preventing its interaction with phosphorylated

STAT1

and

hnRNP C1

/

C2

, which accumulate in the cytoplasm. In

HPV

, while

HPV11 L1

binds Kapβ2/β3 and disrupts cargo import, the viral

HPV16 L2

protein gets imported into nucleus by binding to Kapβ2, Kapβ3 and Kapα/Kapβ1 complex. To inhibit protein import, L protein of

EMCV

hyperphosphorylates Nups and binds Ran.

ICP27

protein of

HSV

interacts with Nup62 and blocks nuclear import of proteins via Kapα/Kapβ1 and Kapβ2 pathways. Disruption of nuclear import of proteins by other viruses is discussed in the text.

Figure 2

Figure 2

Viral disruption of host

mRNA

nuclear export pathways. Host

mRNA

export is coordinated by the

TREX

complex, which consists of

THO

,

UAP56

and

REF

/Aly. The association of

REF

with

mRNA

recruits the

mRNA

export receptor heterodimer

NXF1‐NXT1

, which mediates export of

mRNAs

by interacting with Nups at the

NPC

. Circles surrounding

mRNAs

depict

RNA

‐binding proteins. Viral proteins (depicted as blue starbursts) disrupt

mRNA

nuclear export by interacting with host factors.

IAV NS1

binds and disrupts factors involved in cellular

mRNA

processing and export.

VSV

M protein interacts with Rae1 and Nup98, resulting in

mRNA

nuclear export block.

2Apro

of

PV

and

HRV

cleaves Nups to disrupt

NPC

architecture.

AdV E1B 55K

and

E4orf6

proteins disrupt

NXF1

‐mediated host

mRNA

export by binding to

E1B‐AP5

. Other viruses, such as herpesviruses and

HIV

, utilize cellular transport pathways to promote viral

mRNA

export. The herpesvirus protein

ICP27

facilitates preferential export of viral

mRNAs

through interaction with

REF

/Aly and

NXF1

. The

HIV‐1

Rev protein facilitates nuclear export of unspliced or partially spliced viral

mRNAs

through the Rev‐responsive element (

RRE

), an

RNA

signature on these viral

mRNAs

. Rev‐bound viral

RNA

binds

CRM1

and

RanGTP

and is translocated through the

NPC

.

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