Souza-Costa Luiz P, Santos Felipe R S, Pimenta Jordane C, Queiroz-Junior Celso M, Tana Fernanda L, Teixeira Danielle C, Couto Manoela G G, Oliveira Natalia F M, Pereira Rafaela D, Beltrami Vinicius A, Costa Pedro A C, Lacerda Larisse S B, Andrade-Chaves Josiane T, Guimarães Pedro P G, Aguiar Renato S, Teixeira Mauro M, Costa Vivian V, Franco Luis H
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Belo Horizonte 31270-901, MG, Brazil.
Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Belo Horizonte 31270-901, MG, Brazil.
Pathogens. 2024 Oct 3;13(10):871. doi: 10.3390/pathogens13100871.
The E3 ubiquitin ligase Smurf1 catalyzes the ubiquitination and proteasomal degradation of several protein substrates related to inflammatory responses and antiviral signaling. This study investigated the role of Smurf1 in modulating inflammation induced by Betacoronavirus infection. Bone marrow-derived macrophages (BMDMs) from C57BL/6 (wild-type) or Smurf1-deficient () mice were infected with MHV-A59 to evaluate the inflammatory response in vitro. Smurf1 was found to be required to downregulate the macrophage production of pro-inflammatory mediators, including TNF, and CXCL1; to control viral release from infected cells; and to increase cell viability. To assess the impact of Smurf 1 in vivo, we evaluated the infection of mice with MHV-A59 through the intranasal route. mice infected with a lethal inoculum of MHV-A59 succumbed earlier to infection. Intranasal inoculation with a 10-fold lower dose of MHV-A59 resulted in hematological parameter alterations in mice suggestive of exacerbated systemic inflammation. In the lung parenchyma, Smurf1 expression was essential to promote viral clearance, downregulating IFN-β mRNA and controlling the inflammatory profile of macrophages and neutrophils. Conversely, Smurf1 did not affect IFN-β mRNA regulation in the liver, but it was required to increase TNF and iNOS expression in neutrophils and decrease TNF expression in macrophages. In addition, mice exhibited augmented liver injuries, accompanied by high serum levels of alanine aminotransferase (ALT). These findings suggest that Smurf1 plays a critical role in regulating the inflammatory response in macrophages and attenuating systemic inflammation during Betacoronavirus infection.
E3泛素连接酶Smurf1催化多种与炎症反应和抗病毒信号相关的蛋白质底物的泛素化和蛋白酶体降解。本研究调查了Smurf1在调节β冠状病毒感染诱导的炎症中的作用。用MHV-A59感染来自C57BL/6（野生型）或Smurf1缺陷型（）小鼠的骨髓来源巨噬细胞（BMDM），以评估体外炎症反应。发现Smurf1是下调巨噬细胞促炎介质（包括TNF和CXCL1）产生、控制病毒从感染细胞中释放以及提高细胞活力所必需的。为了评估Smurf1在体内的影响，我们通过鼻内途径评估了小鼠感染MHV-A59的情况。感染致死剂量MHV-A59的小鼠更早死于感染。用低10倍剂量的MHV-A59鼻内接种导致小鼠血液学参数改变，提示全身炎症加剧。在肺实质中，Smurf1表达对于促进病毒清除、下调IFN-β mRNA以及控制巨噬细胞和中性粒细胞的炎症特征至关重要。相反，Smurf1不影响肝脏中IFN-β mRNA的调节，但它是增加中性粒细胞中TNF和iNOS表达以及降低巨噬细胞中TNF表达所必需的。此外，小鼠表现出肝脏损伤加重，伴有血清丙氨酸转氨酶（ALT）水平升高。这些发现表明，Smurf1在调节巨噬细胞炎症反应和减轻β冠状病毒感染期间的全身炎症中起关键作用。
