One of the many ways that viruses invade and infect host cells is by coopting host proteins to help them replicate. The host protein INI1/SMARCB1 is involved in a multitude of essential cellular functions and is used for replication by pathogenic viruses including HIV-1 and SARS-CoV2.
In a study published online on May 12 in Nature Communications, Ganjam Kalpana, Ph.D., and colleagues report that a segment of INI1/SMARCB1’s three-dimensional structure mimics the structure of a portion of HIV-1’s RNA and that the HIV-1 enzyme known as integrase can bind to both. By mimicking viral RNA, the host protein appears to prevent viral integrase from binding to viral RNA—a binding event that may actually impede viral replication by interfering with the release of viral particles from infected cells. The researchers found that HIV-1’s “hijacking” of INI1/SMARCB1 as a binding partner appears to be essential for HIV-1’s ability to successfully form and release its particles; and if interaction between the host protein and viral enzyme is disrupted, the resulting HIV-1 particles have defective structures and are completely non-infectious.
The unprecedented discovery that a host protein facilitates HIV-1 infection by mimicking HIV-1 RNA could lead to novel drugs to inhibit HIV-1 replication. Such drugs could work by simultaneously targeting host and virus protein-protein and protein-RNA interactions. Since INI1/SMARCB1 also functions as a tumor suppressor in cells, the discovery of the protein’s mimicry of RNA could also lead to insights into the mechanisms of tumor suppression and to the development of new drugs for treating cancer.
Dr. Kalpana is professor of genetics and of microbiology & immunology and is the Mark Trauner Faculty Scholar in Neuro-oncology at Einstein. Drs. Updesh Dixit and Savita Bhutoria, two postdoctoral fellows in Dr. Kalpana’s laboratory are co-first authors of the manuscript. It is a collaborative project between structural biologists at Einstein including Drs. Mark Girvin, David Cowburn and Steven Almo and Dr. Kalpana’s laboratory.
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Posted on: Thursday, July 01, 2021