Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication

doi:10.1371/journal.ppat.1011241

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Title:	Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication
Authors:	Kao, Yi-Sheng Wang, Li-Chiu Chang, Po-Chun Lin, Heng-Ming Lin, Yee-Shin Yu, Chia-Yi Chen, Chien-Chin A. Lin, Chiou-Feng Yeh, Trai-Ming A. Wan, Shu-Wen Wang, Jen-Ren A. Ho, Tzong-Shiann Chu, Chien-Chou A. Zhang, Bo-Cheng Chang, Chih-Peng A.
Contributors:	Natl Cheng Kung Univ, Coll Med, Dept Microbiol & Immunol I Shou Univ, Sch Med Natl Cheng Kung Univ, Inst Basic Med Sci, Coll Med Natl Cheng Kung Univ, Ctr Infect Dis & Signaling Res Natl Hlth Res Inst, Natl Inst Infect Dis & Vaccinol Chia Yi Christian Hosp, Ditmanson Med Fdn, Dept Pathol Chia Nan Univ Pharm & Sci, Dept Cosmet Sci Taipei Med Univ, Grad Inst Med Sci, Coll Med Natl Cheng Kung Univ, Coll Med, Dept Med Lab Sci & Biotechnol Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp, Coll Med, Dept Pediat
Keywords:	NF-KAPPA-B CRITICAL ROLES PROTEIN SUPPRESSOR EXPRESSION INFECTION CELLS PHOSPHORYLATION ACTIVATION INHIBITION
Date:	2023
Issue Date:	2024-12-25 11:05:56 (UTC+8)
Publisher:	PUBLIC LIBRARY SCIENCE
Abstract:	Author summaryDengue virus (DENV) can alter cell responses to benefit viral replication. However, most cellular proteins, especially those enhancing viral replication, remains unknown, and their roles in DENV pathogenesis are elusive. Here, we show that integrin-linked kinase (ILK) enhanced DENV infection. ILK binds DENV NS1 and NS3 to induce SOCS3 expression and abrogate STAT1/2-mediated expression of interferon-stimulated genes via the Akt-Erk- NF-kappa B pathway. Knockdown or inhibiting ILK enhances SOCS3 expression and reduces DENV yields in cells. Furthermore, inhibiting ILK in DENV-infected mice significantly decreased viral loads in the mouse brain and mortality. In conclusion, we identified ILK as a potential therapeutic target for DENV infection. Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-kappa B-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection.
Relation:	Plos Pathogens, v.19, n.3
Appears in Collections:	[Offices] 456

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