SAMD9 and SAMD9L (SAMD9/9L) are a pair of human genes that play an important role in innate immunity against viruses and myeloid tumors. Mutations in human SAMD9/9L, that display gain-of-function (GoF) phenotypes, are associated with multisystem developmental disorders characterized by immunodeficiency and a predisposition to myelodysplastic syndromes (MDS) and leukemia. SAMD9/9L are particularly potent in restricting poxvirus replication, and poxviruses have evolved multiple specific inhibitors against these genes. Recently, our lab made a significant discovery that SAMD9 is a poxvirus-activable tRNA endonuclease that specifically cleaves phenylalanine tRNA, revealing tRNA-Phe depletion as an antiviral mechanism and a pathogenic condition in SAMD9/9L disorders. Studies of SAMD9/9L and their viral inhibitors are crucial for understanding poxvirus host tropisms and for developing therapeutic strategies for diseases caused by GoF SAMD9/9L mutations.
