Severe Acute Respiratory Syndrome-associated Coronavirus Nucleocapsid Protein Interacts with Smad3 and Modulates Transforming Growth Factor-β Signaling

Zhao, Xingang; Nicholls, John M.; Chen, Ye-Guang

doi:10.1074/jbc.m708033200

Cited by 188 publications

(192 citation statements)

References 54 publications

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“…Examples include hepatitis B virus pX; hepatitis C virus core protein, NS3 and NS5; Kaposi sarcoma-associated herpesvirus K-bZIP; Epstein-Barr virus LMP1; and severe acute respiratory syndrome-associated coronavirus N protein. [39][40][41][42][43][44] Like HBZ, the HBV pX and severe acute respiratory syndrome N protein enhance the transcriptional responses of TGF-␤. The common strategy used by viruses to modulate TGF-␤ signaling is the direct binding of viral proteins to Smad proteins.…”

Section: Discussionmentioning

confidence: 99%

HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator

Zhao

Satou

Sugata

et al. 2011

Blood

123

113

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Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-␤ (TGF-␤)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-␤ signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-␤ response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-␤. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-␤ signaling. Our results suggest that HBZ, by enhancing TGF-␤ signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence. (Blood. 2011;118(7):1865-1876) IntroductionHuman T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). 1,2 The unique sequence of HTLV-1 between the env region and 3Ј long terminal repeat, denoted the pX region, encodes regulatory (tax and rex) and accessory (p12, p13, and p30) genes in the plus strand. 3 The pleiotropic actions of Tax are thought to play a central role in the early stage of leukemogenesis. 4 However, approximately 60% of fresh ATL cells lack Tax expression because of genetic and epigenetic changes in the HTLV-1 provirus, suggesting that Tax may not be essential for the maintenance of ATL cells in vivo. 5 The HTLV-1 bZIP factor (HBZ), which is encoded by the complementary strand of the HTLV-1 genome, is expressed in all ATL cases and supports the proliferation of ATL cells. 6,7 In addition, HBZ was found to inhibit Tax-mediated activation of viral transcription from the 5Ј-long terminal repeat by heterodimerizing with c-Jun, CREB2, and to selectively suppress the classic pathway of nuclear factor-B by 2 distinct mechanisms. [8][9][10][11] Thus, HBZ has multifunctional roles in cellular signaling and proliferation. Recently, we reported that nonsense mutations in all HTLV-1 genes except HBZ were generated by APOBEC3G before integration of the provirus in ATL cases and HTLV-1 infected persons, indicating that the HBZ gene is essential for leukemogenesis. 12 Transforming growth factor-␤ (TGF-␤) controls a variety of biologic processes, including cell growth, differentiation, apoptosis, development, and immune homeostasis. 13 The Smad proteins, which are mediators of TGF-␤ signaling, transdu...

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Section: Discussionmentioning

confidence: 99%

HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator

Zhao

Satou

Sugata

et al. 2011

Blood

123

113

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“…There is evidence showing that Smad4 is not indispensable for the development of the mammary gland, liver, or pancreas in mice [2,8]. We have demonstrated that the nucleocapsid (N) protein of severe acute respiratory syndromeassociated coronavirus can bind to Smad3, interfere with the complex formation between Smad3 and Smad4, and promote Smad3-p300 complex formation in the nucleus [9], indicating a novel mode of Smad3 effect in a Smad4-independent manner. TIF1g is also found to selectively associate with phosphorylated Smad2/3 in hematopoietic, mesenchymal, and epithelial cells in response to TGF-b and transduce the signal independent of Smad4 to promote erythrogenesis [10].…”

Section: Overview Of Tgf-b Signaling Pathwaysmentioning

confidence: 98%

Regulation of TGF-β signaling by Smad7

Yan¹,

Liu²,

Chen³

2009

ABBS

371

310

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“…We designed a point mutation of the catalytic site (MTMR4-C407S) in which the invariant cysteine residue in the CSDGWDR motif (present within all enzymatically active members of the MTMR superfamily (18)) was substituted by a serine residue by mutation using the QuickChange method (Promega). The various truncations of pCMV-MycSmad3 (pCMV-Myc-MH1, pCMV-Myc-MH1-Linker, pCMVMyc-MH2, pCMV-Myc-Linker-MH2), constitutively active Smad3 plasmid (pRK5-HA-Smad3 (SD)), and constitutively active T␤RI plasmid (pCS2-GGD-HA) used here have been described previously (21). pDsRed2-N1-EEA1 was constructed by subcloning EEA1 cDNA (provided by Dr. X.-J.…”

Section: Methodsmentioning

confidence: 99%

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

Pan

Qin

et al. 2010

Journal of Biological Chemistry

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Homeostasis of Smad phosphorylation at its C-terminal SXS motif is essential for transforming growth factor ␤ (TGF␤) signaling. Whereas it is known that TGF␤ signaling can be terminated by phosphatases, which dephosphorylate R-Smads in the nucleus, it is unclear whether there are any cytoplasmic phosphatase(s) that can attenuate R-Smad phosphorylation and nuclear translocation. Here we demonstrate that myotubularinrelated protein 4 (MTMR4), a FYVE domain-containing dualspecificity protein phosphatase (DSP), attenuates TGF␤ signaling by reducing the phosphorylation level of R-Smads in early endosomes. Co-immunoprecipitation experiments showed that endogenous MTMR4 interacts with phosphorylated R-Smads, and that this interaction is correlated with dephosphorylation of R-Smads. Further analysis showed that overexpression of MTMR4 resulted in the sequestration of activated Smad3 in the early endosomes, thus reducing its nuclear translocation. However, both point mutations at the conserved catalytic site of the phosphatase (MTMR4-C407S) and small interference RNA of endogenous Mtmr4 expression led to sustained Smad3 activation. This work therefore suggests that MTMR4 plays an important role in preventing the overactivation of TGF␤ signaling by dephosphorylating activated R-Smads that have been trafficked to early endosomes. The transforming growth factor ␤ (TGF␤)3 signaling pathway involves two transmembrane serine/threonine kinases, namely type II (T␤RII) and type I TGF␤ receptors (T␤RI) (1, 2). T␤RII, a constitutively active kinase, binds TGF␤ to initiate its heterodimerization with T␤RI. T␤RI then becomes phosphorylated and activates a signaling cascade through a family of intracellular signaling mediators known as Smads.In doing so, T␤RI recruits receptor-regulated Smads (RSmads, including BMP signaling transducers Smad1, -5, and -8 and TGF␤ signaling transducers Smad2, -3) and phosphorylates the two conserved C-terminal serines (SXS) of R-Smads. Activated R-Smads form a trimeric complex with a common mediator Smad (Co-Smad, Smad4), and these complexes translocate into the nucleus to regulate the transcription of an array of target genes (3-7). Recent studies have also indicated that Smad Anchor for Receptor Activation (SARA), an early endosomal protein containing a characteristic FYVE domain (Fab1p, YO1B, Vac1p, and EEA1), serves as an anchor protein by directly recruiting Smad2 to the early endosomes (8, 9) and presenting Smad2 to the internalized T␤RI/II complex (10, 11). Phosphorylated Smad2 then dissociates from SARA and leaves the early endosome. Subsequently, it forms a Smad2-Smad4 complex for nuclear translocation.Despite the fact that TGF␤ signaling activation is surprisingly simple, there are many layers of negative regulation that fine-tune or terminate the signal. The inhibitory Smads (I-Smads, including Smad6 and -7) competitively inhibit the interaction of R-Smads with Smad4 or receptors to provide a negative checkpoint for TGF␤-signaling activation (12). Ubiquitin-dependent degradation of activated...

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Severe Acute Respiratory Syndrome-associated Coronavirus Nucleocapsid Protein Interacts with Smad3 and Modulates Transforming Growth Factor-β Signaling

Cited by 188 publications

References 54 publications

HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator

HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator

Regulation of TGF-β signaling by Smad7

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

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Severe Acute Respiratory Syndrome-associated Coronavirus Nucleocapsid Protein Interacts with Smad3 and Modulates Transforming Growth Factor-β Signaling

Cited by 188 publications

References 54 publications

HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator

HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator

Regulation of TGF-&beta; signaling by Smad7

MTMR4 Attenuates Transforming Growth Factor β (TGFβ) Signaling by Dephosphorylating R-Smads in Endosomes

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Regulation of TGF-β signaling by Smad7