Abstract
Recent studies have begun to elucidate a role for E3 ubiquitin ligases as important mediators of the innate immune response. Our previous work defined a role for the ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) in mouse and human innate immunity. Here, we present novel data describing a role for NKLAM in regulating the immune response to Sendai virus (SeV), a murine model of paramyxoviral pneumonia. NKLAM expression was significantly upregulated by SeV infection. SeV-infected mice that are deficient in NKLAM demonstrated significantly less weight loss than wild type mice. In vivo, Sendai virus replication was attenuated in NKLAM-/- mice. Autophagic flux and the expression of autophagy markers LC3 and p62/SQSTM1 were also less in NKLAM-/- mice. Using flow cytometry, we observed less neutrophils and macrophages in the lungs of NKLAM-/- mice during SeV infection. Additionally, phosphorylation of STAT1 and NFκB p65 was lower in NKLAM-/- than wild type mice. The dysregulated phosphorylation profile of STAT1 and NFκB in NKLAM-/- mice correlated with decreased expression of numerous proinflammatory cytokines that are regulated by STAT1 and/or NFκB. The lack of NKLAM and the resulting attenuated immune response is favorable to NKLAM-/- mice receiving a low dose of SeV; however, at a high dose of virus, NKLAM-/- mice succumbed to the infection faster than wild type mice. In conclusion, our novel results indicate that NKLAM plays a role in regulating the production of pro-inflammatory cytokines during viral infection.
Highlights
Respiratory infections are a significant cause of morbidity and mortality worldwide
NKLAM is an interferon-stimulated gene (ISG) as its expression is increased by IFNβ [16] and IFNγ [5] treatment, but the effect of viral infection or viral nucleic acid mimetics on NKLAM expression is not known
Our current study describes a novel role for RING in between RING (RBR) E3 ubiquitin ligase NKLAM as a component of the innate immune response against viral infection
Summary
Respiratory infections are a significant cause of morbidity and mortality worldwide. Even though there is a wide variety of distinct respiratory viruses that cause human illness, the clinical presentations for viral respiratory infection are remarkably similar. An emerging hypothesis suggests that it is the host response to the virus that accounts for the pathological effects observed during viral infection [1]. The cytokine storm, a dysregulated production of pro-inflammatory cytokines, correlates with lung tissue injury and poor prognosis during. NKLAM regulates cytokine expression in SeV infection decision to submit the work for publication. There was no additional funding received for this study
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