SARS coronavirus papain-like protease up-regulates the collagen expression through non-Samd TGF-β1 signaling

Wang, Ching Ying; Lu, Chien Yi; Li, Shih Wen; Lai, Chien‐Chen; Hua, Chun Hung; Huang, Su; Lin, Ying; Hour, Mann Jen; Lin, Cheng Wen

doi:10.1016/j.virusres.2017.04.008

Cited by 36 publications

(33 citation statements)

References 26 publications

(46 reference statements)

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“…In human lung epithelial cells and mouse models, SARS‐CoV Plpro also upregulated the level of Egr‐1 through the ROS‐induced p38 MAPK and STAT3 activation, leading to the increase in TGF‐β production by direct Egr‐1 interacting with the Egr‐1 binding site located in the TGF‐β promoter region . SARS‐CoV PLpro similarly upmodulated p38 MAPK/STAT3‐mediated expression of Type I collagen in vitro and in vivo, mediated by non‐SMAD TGF‐β signaling including STAT6 activation, correlated with upregulated pulmonary pro‐fibrotic responses . Furthermore, SARS‐CoV nucleocapsid (N) protein inhibited the formation of SMAD3/4 complex, resulting in blocked TGF‐β‐induced apoptosis in SARS‐CoV‐infected host cells.…”

Section: Other Human Virusesmentioning

confidence: 87%

“…100 -enhanced p38 MAPK/STAT3-mediated expression of type I collagen in vitro and in vivo, through non-SMAD TGF-β signaling. 101 N -suppressed TGF-β-induced apoptosis by disrupting SMAD3/SMAD4 complex. 103 -enhanced PAI-1-induced tissue fibrosis via SMAD3/p300 complex promotion.…”

Section: Sars-cov Plpromentioning

confidence: 99%

“…Viral pathogens currently not associated with oncogenesis also modulate the TGF‐β pathway. Severe acute respiratory syndrome (SARS)‐coronavirus (CoV), a RNA virus known to cause outbreak of SARS disease, targets TGF‐β signaling; SARS‐CoV papain‐like protease (Plpro) stimulates the TGF‐β mRNA and protein production and pro‐fibrotic genes expression by the p38 MAPK and ERK1/2‐mediated pathways in human promonocytes (Figure ) . In human lung epithelial cells and mouse models, SARS‐CoV Plpro also upregulated the level of Egr‐1 through the ROS‐induced p38 MAPK and STAT3 activation, leading to the increase in TGF‐β production by direct Egr‐1 interacting with the Egr‐1 binding site located in the TGF‐β promoter region .…”

Section: Other Human Virusesmentioning

confidence: 99%

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Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Mirzaei

Faghihloo

2018

Reviews in Medical Virology

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Transforming growth factor-β (TGF-β) signaling pathway is a key network in cell signaling that controls vital processes such as proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and migration, thus acting as a double-edged sword in normal development and diseases, in particular organ fibrosis, vascular disorders, and cancer. Early in tumorigenesis, the pathway exerts anti-tumor effects through suppressing cell cycle and inducing apoptosis, while during late stages, it functions as a tumor promoter by enhancing tumor invasiveness and metastasis. This signaling pathway can be perturbed by environmental and genetic factors such as microbial interference and mutation, respectively. In this way, the present review describes the modulation of the TGF-β pathway by oncogenic human viral pathogens and other viruses. The main mechanisms by which viruses interferes with TGF-β signaling seems to be through (1) the alteration of either TGF-β protein expression or activation, (2) the modulation of the TGF-β receptors or SMADs factors (by interfering with their levels and functions), (3) the alteration of none-SMAD pathways, and (4) indirect interaction with the pathway by the modulation of transcriptional co-activator/repressor and regulators of the pathway. Given the axial role of this pathway in tumorigenesis, it can be regarded as an attractive target for cancer therapy. Hence, further investigations on this subject may represent molecular targets among either TGF-β signaling molecules or viral factors for the treatment and management of viral infection consequences such as cancer.

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Section: Other Human Virusesmentioning

confidence: 87%

Section: Sars-cov Plpromentioning

confidence: 99%

Section: Other Human Virusesmentioning

confidence: 99%

See 1 more Smart Citation

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Mirzaei

Faghihloo

2018

Reviews in Medical Virology

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“…These effects are mediated by partly mediated by the protease activity but mainly derive from the deubiquitinating and deIGSgylating functions associated with fulllength NSP3 [20][21][22]. SARS-CoV PLpro has also been reported to also activate TGF-β1 signalling [23] or down-regulate p53 [24]. Similarly, 3CLpro from the feline coronavirus, feline infectious peritonitis virus (FIPV), inhibits type I interferon signalling through cleavage of NEMO [25], while the porcine deltacoronavirus (PDCoV) 3CLpro cleaves STAT2.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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“…SARS-CoV papain-like protease (PLpro) induces Egr-1 dependent up-regulation of the transforming growth factor-β 1 (TGF-β 1) through the ROS/p38/MAPK/STAT3 pathway, thereby up-regulating the pro-fibrotic responses in vitro and in vivo 53 . SARS-CoV PLpro also caused the change in the ubiquitination profile of Rho GTPase family proteins and plays a role in the TGF-β 1-dependent expression of Type I collagen via activating STAT6 pathway 54 . Also, SARS-CoV nucleocapsid (N) protein potentiates TGF-β 1-induced expression of plasminogen activator inhibitor-1 and attenuates the Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial cells 55 .…”

Section: Host Proteins and Corresponding Viral Proteinmentioning

confidence: 99%

Understanding Structural Malleability of the SARS-CoV-2 Proteins and their Relation to the Comorbidities

Sen

Dey

Bandyopadhyay

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease (CoVID-19), is a part of the β-coronaviridae family. In comparison with two other members of this family of coronaviruses infecting humans (SARS-CoV and Middle East Respiratory Syndrome (MERS) CoV), SARS-CoV-2 showed the most severe effects on the entire Earth population causing world-wide CoVID-19 pandemic. SARS-CoV-2 contains five major protein classes, such as four structural proteins (Nucleocapsid (N), Membrane (M), Envelop (E), and Spike Glycoprotein (S)) and Replicase polyproteins (R), which are synthesized as two polyproteins (ORF1a and ORF1ab) that are subsequently processed into 12 nonstructural proteins by three viral proteases. All these proteins share high sequence similarity with their SARS-CoV counterparts. Due to the severity of the current situation, most of the SARS-CoV-2-related research is focused on finding therapeutic solutions and the analysis of comorbidities during infection. However, studies on the peculiarities of the amino acid sequences of viral protein classes and their structure space analysis throughout the evolutionary time-frame are limited. At the same time, due to their structural malleability, viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins, which may lead to comorbidities during the infection and at the post infection stage. To fill these gaps, we conducted the evolutionary sequence-structure analysis of the viral protein classes to evaluate the rate of their evolutionary malleability. We also looked at the intrinsic disorder propensities of these viral proteins and confirmed that although they typically do not have long intrinsically disordered regions (IDRs), all of them have at least some levels of intrinsic disorder. Furthermore, short IDRs found in viral proteins are extremely effective and prioritize the proteins for host cell interactions, which may lead to host cell dysfunction. Next, the associations of viral proteins with the host cell proteins were studied, and a list of diseases which are associated with such host cell proteins was developed. Other than the usual set of diseases, we have identified some maladies, which may happen after the recovery from the infections. Comparison of the expression rates of the host cell proteins during the diseases suggested the existence of two distinct classes. First class includes proteins, which are directly associated with certain sets of diseases, where they have shared similar activities. Second class is related to the cytokine storm-mediated pro-inflammation (already known for its role in acute respiratory distress syndrome, ARDS), and neuroinflammation may trigger some of the neurological malignancies and neurodegenerative and neuropsychiatric diseases. Finally, since the transmembrane serine protease 2 (TMPRSS2), which is one of the leading proteins associated with the viral uptake, is an androgen-mediated protein, our study suggested that males and postmenopausal females can be more susceptible to the SARS-CoV-2 infection.

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SARS coronavirus papain-like protease up-regulates the collagen expression through non-Samd TGF-β1 signaling

Cited by 36 publications

References 26 publications

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Understanding Structural Malleability of the SARS-CoV-2 Proteins and their Relation to the Comorbidities

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