SAMD9/9L Innate Immunity: Antiviral Mechanisms and Evolutionary Trade-Offs of Multidomain Proteins.

Sterile alpha motif domain-containing 9 and 9-like (SAMD9/9L) are large multidomain proteins with antiviral innate immune and cellular homeostasis functions. Initially characterized as tumor suppressors, they are now also recognized as antiviral restriction factors against diverse viruses, including poxviruses, lentiviruses, rotaviruses, and flaviviruses. Their architecture notably combines central regulatory P-loop NTPase and sensing tetratricopeptide repeat domains with an N-terminal AlbA_2 nuclease effector, which performs a protein translational shutdown through transfer RNA cleavage. Structural and functional SAMD9/9L analogs in prokaryotic antiviral systems, such as antiviral STAND (Avs), reveal ancient convergent strategies for defense across kingdoms of life. In humans, gain-of-function and loss-of-function mutations may lead to severe multisystem syndromes (e.g., MIRAGE, ataxia-pancytopenia). Mutants with increased antiviral functions may have detrimental effects on cell homeostasis. This trade-off underscores the evolutionary tension between antiviral immunity and cellular integrity. Here, we review the molecular mechanisms of SAMD9/9L-mediated antiviral restriction, their genetic associations with disease, and their evolutionary conflicts with viruses. Yet, critical gaps remain in understanding SAMD9/9L regulation, activation, and functional interplay with viral and host factors. Exploring the evolutionary immunology of SAMD9/9L not only illuminates fundamental immune trade-offs but also may have translational applications against infectious diseases, autoimmunity, and cancer.