RNase L

A new study uncovers how a protein, APOBEC3B, could protects cells against many different types of RNA viruses like respiratory syncytial virus (RSV), SARS-CoV2, influenza virus, poliovirus and measles, helping to prevent disease. A new University of California, Irvine-led study uncovers how a protein, APOBEC3B, could protects cells against many different types of RNA viruses like respiratory syncytial virus (RSV), SARS-CoV2, influenza virus, poliovirus and measles, helping to prevent disease. The study was published in Nature Communications. Titled, "APOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection," the study findings provide an understanding of how lung cells, in particular, protect themselves against RNA viral infection. This new discovery is essential to developing future therapies to limit viral infection and improve the health of patients with chronic lung disease. Respiratory syncytial virus (RSV), SARS-CoV2, influenza virus, poliovirus, and measles -- all single-stranded RNA viruses -- are some examples of highly contagious diseases transmitted by respiratory aerosols that commonly infect lung cells. "Patients with chronic lung diseases, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease and interstitial lung diseases, are more susceptible to respiratory lung infections. These viral infections can further contribute to disease progression," said Remi Buisson, PhD, assistant professor in the UCI School of Medicine Department of Biological Chemistry. "An exciting part of our finding fills a critical knowledge gap by illuminating how APOBEC3B can promote innate immune responses in host cells without generating mutations in the virus genomes and promoting viral evolution." In this study, graduate students Lavanya Manjunath and Sunwoo Oh, both at UCI School of Medicine in the Buisson Laboratory, utilized different RNA virus models, including Sendai virus, poliovirus, and Sindbis virus as tools to determine how APOBEC3B regulates innate immune signaling in response to viral infection. Moreover, they found that APOBEC3B is recruited to stress granules through its interaction with PABPC1 to prevent stress granule destabilization and protect mRNAs associated with stress granules from an RNA endonuclease RNase L that cleave RNAs in host cells. "We propose that APOBEC3B, in addition to its canonical role to edit viral genomes, functions with PABPC1 as important innate immunity mediators, protecting cells at different steps of the innate immune response against viral infections," said Buisson. More research is needed to develop strategies to prevent RNA viral infection. "Our next steps are to determine the detailed mechanism of how APOBEC3B recognizes viral genome to promote an innate immune response and prevent viral replication," said Buisson. "The goal is to identify how RNA viruses developed resistance mechanisms to counteract APOBEC3B functions and escape host cell defense." The study was funded by support from the National Institutes of Health.

New research findings have revealed an underlying genetic cause for why some children who have had COVID-19 infection develop Multisystem Inflammatory Syndrome in Children (MIS-C), a rare but potentially life-threatening disease. New research findings have revealed an underlying genetic cause for why some children who have had COVID-19 infection develop Multisystem Inflammatory Syndrome in Children (MIS-C), a rare but potentially life-threatening disease. The findings are the first potential genetic cause identified for MIS-C, a disease that typically occurs about four weeks after COVID-19 infection and has broad symptoms such as fever, vomiting and inflammation of the heart muscle that can lead to hospitalization. States have reported about 9,000 MIS-C cases, with 71 deaths, according to most recent Centers for Disease Control and Prevention numbers. The results, published in Science, are rooted in more than 40 years of research from Robert Silverman, Ph.D., of Cleveland Clinic Lerner Research Institute's Department of Cancer Biology. The study, led by Rockefeller University, found genetic mutations to the proteins OAS and RNase L increased the inflammatory response in some immune cell types. That change can cause inflammation in multiple organs, including the heart, lungs, kidneys and gastrointestinal tract. In the study, mutations were identified in a small subset of children with MIS-C. OAS proteins are induced by interferons, as a first line of defense against viruses. After sensing viral double-stranded RNA, OAS proteins activate RNase L to prevent the virus from multiplying and spreading. "RNase L acts like scissors to cut up messenger RNA that gets translated into proteins, including proteins known as cytokines that cause inflammation," Dr. Silverman said. "The autosomal recessive mutations in MIS-C either prevent the scissors from operating (OAS mutations) or prevent the scissors from being made at all (RNase L mutations). These findings offer important insights about how OAS-RNase L can protect against this severe unexplained complication of COVID-19." Dr. Silverman's lab, which studies the role of interferons in immune responses with a focus on the OAS-RNase L pathway, collaborated with a team at Rockefeller University led by Jean-Laurent Casanova, M.D., Ph.D. Dr. Casanova's team found the mutations in part through analyzing DNA sequence data from MIS-C patients in comparison to other children who were infected with COVID-19 but did not contract MIS-C. "Our findings improve the understanding of MIS-C by clarifying the molecular, cellular and immunological basis of the disease," said Dr. Casanova. "We identified the mutations through analyzing DNA sequence data from MIS-C patients in comparison to other children who were infected with COVID-19 but did not contract MIS-C. One of the key research questions was whether increased virus multiplication or an exaggerated inflammatory response led to MIS-C in the cases with the mutations. Our results support the latter explanation." As part of an international collaboration, Dr. Silverman's team determined what the specific effects of the mutations were on the pathway. That included screening dozens of mutant genes, identifying the effects on RNA and then correlating the results with the disease. "Our team took what I had learned over the years about these enzymes to get the functional data that the study needed," said Dr. Silverman. "Essentially, this validated the effects these mutations had on function." Dr. Silverman's lab also contributed reagents not commercially available, synthesizing a small molecule that switches on RNase L and makes it cleave RNA. The study determined that these mutations led to an exacerbated inflammatory response at a molecular level, according to the paper. Knowledge about these mutations and how it affects immune mechanisms could provide more information on other diseases that cause chronic inflammation, like Kawasaki disease, which presents similarly to MIS-C. Funding to Cleveland Clinic: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award R01AI104887.