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

Abstract

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.

Antiviral immunity via telomerase-like reverse transcription in bacteria
Stephen Tang, Josephine L. Ramirez, Qixiang He +11
Nature12 Oct 2026Peer-reviewedLicence not statedFull text9 citedEcologyOpenAlex
The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation
Pham Thuy Tien Vo, Julien Cicero, Zichen Wang +17
Cell Reports1 Oct 2026Peer-reviewedCC BY 4.0ImmunologyCrossref
High-Throughput Screening Identifies Proteasome Inhibitors as Potentiators of Type III Interferon JAK-STAT Signaling and Antiviral Immunity
J.-P. Parisien, C. O Leary, S. Shabani +5
bioRxiv12 Oct 2026PreprintCC BYFull textImmunologybioRxiv
EV-B 3D polymerase remodels viral populations through 5′UTR recombination to subvert cardiac antiviral innate immunity
Marie Glenet, Laetitia Heng, Anne-Laure Lebreil +4
PLoS Pathogens24 Jul 2026Peer-reviewedCC BY 4.0Full textGeneral biologyHAL
c-FLIP loss links arrest of gene expression to TNFα-dependent antiviral guard immunity
Matthew Sonnett, Sanne Boersma, Madeline E. Ward +8
Proceedings of the National Academy of Sciences of the United States of America22 Oct 2026Peer-reviewedCC BY 4.0Full textSystems & synthetic biologyPMC

Cite

BibTeX RIS

BibTeX

@article{demeure2026samd99l,
  title = {{SAMD9/9L Innate Immunity: Antiviral Mechanisms and Evolutionary Trade-Offs of Multidomain Proteins}},
  author = {Rémi Demeure and Francesca Fiorini and Lucie Etienne and Alexandre Legrand},
  journal = {Annual Review of Virology},
  year = {2026},
  month = sep,
  doi = {10.1146/annurev-virology-100424-105122},
  url = {https://hal.science/hal-05775680v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - JOUR
TI  - SAMD9/9L Innate Immunity: Antiviral Mechanisms and Evolutionary Trade-Offs of Multidomain Proteins
AU  - Rémi Demeure
AU  - Francesca Fiorini
AU  - Lucie Etienne
AU  - Alexandre Legrand
PY  - 2026
DA  - 2026/09/25
JO  - Annual Review of Virology
DO  - 10.1146/annurev-virology-100424-105122
UR  - https://hal.science/hal-05775680v1
AB  - 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.
SN  - 2327-056X
SN  - 2327-0578
ER  -

Abstract

Related

Cite