Search results
Items: 13
1.
Yuan H, You J, You H, Zheng C.
J Virol. 2018 Sep 12;92(19). pii: e01161-18. doi: 10.1128/JVI.01161-18. Print 2018 Oct 1.
Type I interferons
(IFNs), as major components of the innate immune system, play a vital
role in host resistance to a variety of pathogens. Canonical signaling
mediated by type I IFNs activates the Janus kinase-signal transducer and
activator of transcription (JAK-STAT) pathway through binding to the
IFN-α/β receptor (IFNAR), resulting in transcription of IFN-stimulated
genes (ISGs). However, viruses have evolved multiple strategies to evade
this process. Here, we report that herpes
simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates
the type I IFN-mediated signaling pathway independent of its deubiquitinase
(DUB) activity. In this study, ectopically expressed UL36USP inhibited
IFN-β-induced activation of ISRE promoter and transcription of ISGs, and
overexpression of UL36USP lacking DUB activity did not influence this
effect. Furthermore, UL36USP was demonstrated to antagonize
IFN-β-induced activation of JAKs and STATs via specifically binding to
the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2.
More importantly, knockdown of HSV-1 UL36USP restored the formation of
JAK1-IFNAR2 complex. These findings underline the roles of
UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated
signaling pathway and reveal a novel evasion mechanism of antiviral
innate immunity by HSV-1.IMPORTANCE Type I IFNs mediate
transcription of numerous antiviral genes, creating a remarkable
antiviral state in the host. Viruses have evolved various mechanisms to
evade this response. Our results indicated that HSV-1 encodes a
ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I
IFN-mediated signaling. UL36USP was identified to significantly inhibit
IFN-β-induced signaling independent of its deubiquitinase
(DUB) activity. The underlying mechanism of UL36USP antagonizing type I
IFN-mediated signaling was to specifically bind with IFNAR2 and
disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP
as a crucial suppressor for HSV-1 to evade type I IFN-mediated
signaling. Our findings also provide new insights into the innate immune
evasion by HSV-1 and will facilitate our understanding of host-virus
interplay. Copyright © 2018 American Society for Microbiology.KEYWORDS:
HSV-1; IFNAR2; UL36USP; type I IFN-mediated signaling
Free PMC Article
2.
Bhattacharya S, Chakraborty D, Basu M, Ghosh MK.
Signal Transduct Target Ther. 2018 Jun 29;3:17. doi: 10.1038/s41392-018-0012-y. eCollection 2018.
3.
Cai J, Chen HY, Peng SJ, Meng JL, Wang Y, Zhou Y, Qian XP, Sun XY, Pang XW, Zhang Y, Zhang J.
FASEB J. 2018 Oct;32(10):5238-5249. doi: 10.1096/fj.201700473RR. Epub 2018 Apr 24.
Ubiquitination and
deubiquitination are important post-translational regulatory mechanisms
responsible for fine tuning the antiviral signaling. In this study, we
identified a deubiquitinase, the ubiquitin-specific peptidase 7/herpes
virus associated ubiquitin-specific protease (USP7/HAUSP) as an
important negative modulator of virus-induced signaling. Overexpression
of USP7 suppressed Sendai virus and polyinosinic-polycytidylic acid and
poly(deoxyadenylic-deoxythymidylic)-induced ISRE and IFN-β activation,
and enhanced virus replication. Knockdown or knockout of endogenous USP7
expression had the opposite effect. Coimmunoprecipitation assays showed
that USP7 physically interacted with tripartite motif (TRIM)27. This
interaction was enhanced after SeV infection. In addition, TNF
receptor-associated factor family member-associated NF-kappa-B-binding
kinase (TBK)-1 was pulled down in the TRIM27-USP7 complex.
Overexpression of USP7 promoted the ubiquitination and degradation of
TBK1 through promoting the stability of TRIM27. Knockout of endogenous
USP7 led to enhanced TRIM27 degradation and reduced TBK1 ubiquitination
and degradation, resulting in enhanced type I IFN signaling. Our
findings suggest that USP7 acts as a negative regulator in antiviral
signaling by stabilizing TRIM27 and promoting the degradation of
TBK1.-Cai, J., Chen, H.-Y., Peng, S.-J., Meng, J.-L., Wang, Y., Zhou,
Y., Qian, X.-P., Sun, X.-Y., Pang, X.-W., Zhang, Y., Zhang, J.
USP7-TRIM27 axis negatively modulates antiviral type I IFN signaling.
4.
Dong X, Guan J, Zheng C, Zheng X.
J Biol Chem. 2017 May 19;292(20):8472-8483. doi: 10.1074/jbc.M117.778076. Epub 2017 Mar 27.
Abstract. Herpes
simplex virus 1 (HSV-1) infection manipulates distinct host DNA-damage
responses to facilitate virus proliferation, but the molecular
mechanisms remain to be elucidated. One possible HSV-1 target might be
DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS)
pathway. In TLS, proliferating cell nuclear antigen (PCNA) is
monoubiquitinated in response to DNA damage-caused replication fork
stalling. Ubiquitinated PCNA then facilitates the error-prone DNA
polymerase η (polη)-mediated TLS, allowing the fork to bypass damaged
sites. Because of the involvement of PCNA ubiquitination in DNA-damage
repair, we hypothesized that the function of PCNA might be altered by
HSV-1. Here we show that PCNA is a substrate of the HSV-1 deubiquitinase
UL36USP, which has previously been shown to be involved mainly in virus
uptake and maturation. In HSV-1-infected cells, viral
infection-associated UL36USP consistently reduced PCNA ubiquitination.
The deubiquitination of PCNA inhibited the formation of polη foci and
also increased cell sensitivity to DNA-damage agents. Moreover, the
catalytically inactive mutant UL36C40A failed to deubiquitinate PCNA. Of
note, the levels of virus marker genes increased strikingly in cells
infected with wild-type HSV-1, but only moderately in UL36C40A mutant
virus-infected cells, indicating that the UL36USP deubiquitinating
activity supports HSV-1 virus replication during infection. These
findings suggest a role of UL36USP in the DNA damage-response pathway.© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. KEYWORDS: DNA
damage response; DNA polymerase; UL36USP; deubiquitylation
(deubiquitination); herpesvirus; proliferating cell nuclear antigen
(PCNA); translesion synthesis DOI: 10.1074/jbc.M117.778076
Free PMC Article
5.
Ye R, Su C, Xu H, Zheng C.
J Virol. 2017 Feb 14;91(5). pii: e02417-16. doi: 10.1128/JVI.02417-16. Print 2017 Mar 1.
The DNA sensing pathway triggers
innate immune responses against DNA virus infection, and NF-κB signaling
plays a critical role in establishing innate immunity. We report here
that the herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is a deubiquitinase
(DUB), antagonizes NF-κB activation, depending on its DUB activity. In
this study, ectopically expressed UL36USP blocked promoter activation of
beta interferon (IFN-β) and NF-κB induced by cyclic GMP-AMP synthase
(cGAS) and stimulator of interferon genes (STING). UL36USP restricted
NF-κB activation mediated by overexpression of STING, TANK-binding
kinase 1, IκB kinase α (IKKα), and IKKβ, but not p65. UL36USP was also
shown to inhibit IFN-stimulatory DNA-induced IFN-β and NF-κB activation
under conditions of HSV-1 infection. Furthermore, UL36USP was
demonstrated to deubiquitinate IκBα and restrict its degradation and,
finally, abrogate NF-κB activation. More importantly, the recombinant
HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed
to cleave polyubiquitin chains on IκBα. For the first time, UL36USP was
shown to dampen NF-κB activation in the DNA sensing signal pathway to
evade host antiviral innate immunity.IMPORTANCE It has been
reported that double-stranded-DNA-mediated NF-κB activation is critical
for host antiviral responses. Viruses have established various
strategies to evade the innate immune system. The N terminus of the
HSV-1 UL36 gene-encoded protein contains the DUB domain and is conserved
across all herpesviruses. This study demonstrates that UL36USP
abrogates NF-κB activation by cleaving polyubiquitin chains from IκBα
and therefore restricts proteasome-dependent degradation of IκBα and
that DUB activity is indispensable for this process. This study expands
our understanding of the mechanisms utilized by HSV-1 to evade the host
antiviral innate immune defense induced by NF-κB signaling.
Copyright © 2017 American Society for Microbiology.KEYWORDS:
DNA sensor; HSV-1; IκBα; NF-κB; UL36
Free PMC Article
6.
Carrà G, Panuzzo C, Crivellaro S, Morena D, Taulli R, Guerrasio A, Saglio G, Morotti A.
Oncol Lett. 2016 Nov;12(5):3123-3126. Epub 2016 Sep 1.
Philadelphia chromosome-positive (Ph+)
acute lymphoblastic leukemia (ALL) is driven by the p190 breakpoint
cluster region (BCR)-ABL isoform. Although effectively targeted by
BCR-ABL tyrosine kinase inhibitors (TKIs), ALL is associated with a less
effective response to TKIs compared with chronic myeloid leukemia.
Therefore, the identification of additional genes required for ALL
maintenance may provide possible therapeutic targets to aid the
eradication of this cancer. The present study demonstrated that p190
BCR-ABL is able to interact with the deubiquitinase
herpesvirus-associated ubiquitin-specific protease (HAUSP), which in
turn affects p53 protein stability. Notably, the inhibition of HAUSP
with small molecule inhibitors promoted the upregulation of p53 protein
levels. These results suggest that HAUSP inhibitors may harbor
clinically relevant implications in the treatment of Ph+ ALL. KEYWORDS:
BCR-ABL;
acute lymphoblastic leukemia; herpesvirus-associated ubiquitin-specific
protease; herpesvirus-associated ubiquitin-specific protease
inhibitors; p190; p53 DOI: 10.3892/ol.2016.5073
Free PMC Article
7.
Campbell EM, Weingart J, Sette P, Opp S, Sastri J, O'Connor SK, Talley S, Diaz-Griffero F, Hirsch V, Bouamr F.
J Virol. 2015 Dec 16;90(4):1849-57. doi: 10.1128/JVI.01948-15. Print 2016 Feb 15.
- PMID:
- 26676782
8.
Bhattacharya S, Ghosh MK.
FEBS J. 2014 Jul;281(13):3061-78. doi: 10.1111/febs.12843. Epub 2014 Jun 10.
Tumor suppressor
retinoblastoma-associated protein (Rb) is an important cell cycle
regulator, arresting cells in early G1. It is commonly inactivated in
cancers and its level is maintained during the cell cycle. Rb is
regulated by various post-translational modifications such as
phosphorylation, acetylation, ubiquitination and so on. Several E3
ligases including murine double minute 2 (MDM2) promote the degradation
of Rb. This study focuses on the role of HAUSP (herpes
virus associated ubiquitin specific protease) on Rb. Here, we show that
HAUSP colocalizes and interacts with Rb to stabilize it from
proteasomal degradation by removing wild-type and K48-linked ubiquitin
chains in human embryonic kidney 293 (HEK293) cells. HAUSP
deubiquitinates Rb in vivo and in vitro, leading to an increased cell
population in the G1 phase. Hence, HAUSP is a novel deubiquitinase
for Rb. Immunohistochemistry, western blotting and cell-based assays
show that HAUSP is overexpressed in glioma and contributes towards
glioma progression. However, HAUSP activity on Rb is abrogated in glioma
(cancer), where these two proteins show an inverse relationship. MDM2
(a known substrate of HAUSP) serves as a better target for
HAUSP-mediated deubiquitination in cancer cells, facilitating
degradation of Rb and oncogenic progression. This novel regulatory axis
is proteasome mediated, p53 independent, and the level of MDM2 is
critical. The shift in equilibrium by differential deubiquitination in
regulation of Rb explains a subtle difference existing between normal
and cancer cells. This leads to speculation about a new possibility for
distinguishing cancer cells from normal cells at the molecular level,
which may be investigated for therapeutic intervention in the future.
© 2014 FEBS. KEYWORDS:
Rb; deubiquitination; glioma; herpes virus associated ubiquitin specific protease; murine double minute 2. DOI: 10.1111/febs.12843
Free PMC Article
9.
van
Gent M, Braem SG, de Jong A, Delagic N, Peeters JG, Boer IG, Moynagh
PN, Kremmer E, Wiertz EJ, Ovaa H, Griffin BD, Ressing ME.
PLoS Pathog. 2014 Feb 20;10(2):e1003960. doi: 10.1371/journal.ppat.1003960. eCollection 2014 Feb.
Abstract
Viral infection
triggers an early host response through activation of pattern
recognition receptors, including Toll-like receptors (TLR). TLR
signaling cascades induce production of type I interferons and
proinflammatory cytokines involved in establishing an anti-viral state
as well as in orchestrating ensuing adaptive immunity. To allow
infection, replication, and persistence, (herpes)viruses
employ ingenious strategies to evade host immunity. The human
gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA
virus persistently carried by more than 90% of adults worldwide. It is
the causative agent of infectious mononucleosis and is associated with
several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and
TLR9. Interestingly, both the expression of and signaling by TLRs is
attenuated during productive EBV infection. Ubiquitination plays an
important role in regulating TLR signaling and is controlled by
ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes
three proteins reported to exert in vitro deubiquitinase
activity. Using active site-directed probes, we show that one of these
putative DUBs, the conserved herpesvirus large tegument protein BPLF1,
acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is
expressed during the late phase of lytic EBV infection and is
incorporated into viral particles. The N-terminal part of the large
BPLF1 protein contains the catalytic site for DUB activity and
suppresses TLR-mediated activation of NF-κB at, or downstream of, the
TRAF6 signaling intermediate. A catalytically inactive mutant of this
EBV protein did not reduce NF-κB activation, indicating that DUB
activity is essential for attenuating TLR signal transduction. Our
combined results show that EBV employs deubiquitination of signaling
intermediates in the TLR cascade as a mechanism to counteract innate
anti-viral immunity of infected hosts DOI: 10.1371/journal.ppat.1003960 [Indexed for MEDLINE]
10.
Wang S, Wang K, Li J, Zheng C.
J Virol. 2013 Nov;87(21):11851-60. doi: 10.1128/JVI.01211-13. Epub 2013 Aug 28.
11.
Bronner C.
Sci Signal. 2011 Jan 25;4(157):pe3. doi: 10.1126/scisignal.2001764.
Inheritance of DNA methylation
patterns is a key mechanism involved in epigenetic cell memory
transmission from mother cell to daughter cell. This occurs due to
cooperation between the DNA methyltransferase DNMT1 and the ubiquitin
ligase UHRF1 (ubiquitin-like, containing plant homeo domain and RING
finger 1) in a macromolecular complex. Newly identified members of this
complex are the acetyltransferase Tip60 (Tat-interactive protein) and
the deubiquitinase HAUSP (herpes
virus-associated ubiquitin specific protease), which exert tight
regulation of DNMT1 abundance through a ubiquitylation-dependent
process. It is important to determine how all of these actors
communicate with each other and what signals coordinate their
communication. In the case of DNMT1, the balance of UHRF1 and HAUSP
activities might be influenced by the local environment, such as histone
code, cell-cycle status, and local DNA methylation status.DOI: 10.1126/scisignal.2001764
13.
Kim ET, Oh SE, Lee YO, Gibson W, Ahn JH.
J Virol. 2009 Dec;83(23):12046-56. doi: 10.1128/JVI.00411-09. Epub 2009 Sep 16.
