SAMD9 and SAMD9L (SAMD9/9L) are large cytosolic proteins essential for hematopoietic homeostasis and antiviral defense (1–3). Germline gain-of-function (GoF) mutations in SAMD9/9L cause severe multisy...

A search for analogues of the human SAMD9/9L antiviral genes identifies convergent evolution of this gene family in the bacterial and animal kingdoms, with species-specific and recent genomic signatur...

Nature Ecology & Evolution - A search for analogues of the human SAMD9/9L antiviral genes identifies convergent evolution of this gene family in the bacterial and animal kingdoms, with...

Dans une étude publiée dans Nature Ecology and Evolution, des scientifiques montrent que les gènes SAMD9 et SAMD9L, a

Poxviruses have life cycles exclusively in the cytoplasm. With many immunoregulatory proteins manipu

MIRAGE syndrome is a rare multisystem disorder caused by gain-on-function SAMD9 variants. Kidney biopsies in some MIRAGE syndrome patients have shown glomerular sclerosis or interstitial nephritis. A…

Researchers discovered that interferon-stimulated SAMD9L restricts HIV-1 and other lentiviruses by inhibiting viral translation and endosomal trafficking, while SAMD9 enhances HIV-1 replication.

by Marion Cannac, Jim Zoladek, Inès Bribes, Mathis Fresneau--Resende, Alexandre Legrand, Rémi Demeure, Eva Zusinaite, Andres Merits, Lucie Etienne, Sébastien Nisole Interferon-stimulated genes (ISGs) play a pivotal role in the innate immune response to viral infection. Among them, SAMD9 and its paralog SAMD9L have recently emerged as important antiviral effectors with translation-inhibitory activity. While both proteins restrict poxvirus, rotavirus and reovirus replication, only SAMD9L has been shown to inhibit HIV and other lentiviruses. In this study, we identify human SAMD9L as a potent and broad-spectrum restriction factor that targets multiple medically relevant flaviviruses, including West Nile virus (WNV), Zika virus (ZIKV), dengue virus (DENV), and Usutu virus (USUV). Exogenous expression of SAMD9L, but not SAMD9, efficiently suppressed replication of all tested flaviviruses. Furthermore, its knockdown in human myeloid cells, including microglial cells and primary macrophages, impaired the antiviral activity of type I interferon, identifying SAMD9L as a key antiviral ISG in primary target cells of flavivirus infection. Mechanistically, we demonstrate that SAMD9L inhibits viral replication by targeting the translation of flaviviral RNA, and that this activity depends on its Schlafen-like ribonuclease domain, previously implicated in the inhibition of HIV-1 translation. Interestingly, although SAMD9 does not inhibit flavivirus replication, it is able to repress the translation of flaviviral RNA outside the context of infection, suggesting that its activation may be virus-specific or that flaviviruses have evolved mechanisms to evade or counteract SAMD9’s antiviral activity. Finally, we confirm that SAMD9 and SAMD9L overexpression induces activation of the innate immune response. However, this immunostimulatory function is dispensable for SAMD9L-mediated antiviral activity, since SAMD9L is able to restrict flavivirus replication independently of innate immune activation. Together, our findings broaden the known antiviral repertoire of SAMD9L, establish its essential role in restricting flavivirus replication via translational repression, and highlight its function as a key component of the cellular defenses against flaviviruses in myeloid cells.

by Marion Cannac, Jim Zoladek, Inès Bribes, Mathis Fresneau--Resende, Alexandre Legrand, Rémi Demeure, Eva Zusinaite, Andres Merits, Lucie Etienne, Sébastien Nisole Interferon-stimulated genes (ISGs) play a pivotal role in the innate immune response to viral infection. Among them, SAMD9 and its paralog SAMD9L have recently emerged as important antiviral effectors with translation-inhibitory activity. While both proteins restrict poxvirus, rotavirus and reovirus replication, only SAMD9L has been shown to inhibit HIV and other lentiviruses. In this study, we identify human SAMD9L as a potent and broad-spectrum restriction factor that targets multiple medically relevant flaviviruses, including West Nile virus (WNV), Zika virus (ZIKV), dengue virus (DENV), and Usutu virus (USUV). Exogenous expression of SAMD9L, but not SAMD9, efficiently suppressed replication of all tested flaviviruses. Furthermore, its knockdown in human myeloid cells, including microglial cells and primary macrophages, impaired the antiviral activity of type I interferon, identifying SAMD9L as a key antiviral ISG in primary target cells of flavivirus infection. Mechanistically, we demonstrate that SAMD9L inhibits viral replication by targeting the translation of flaviviral RNA, and that this activity depends on its Schlafen-like ribonuclease domain, previously implicated in the inhibition of HIV-1 translation. Interestingly, although SAMD9 does not inhibit flavivirus replication, it is able to repress the translation of flaviviral RNA outside the context of infection, suggesting that its activation may be virus-specific or that flaviviruses have evolved mechanisms to evade or counteract SAMD9’s antiviral activity. Finally, we confirm that SAMD9 and SAMD9L overexpression induces activation of the innate immune response. However, this immunostimulatory function is dispensable for SAMD9L-mediated antiviral activity, since SAMD9L is able to restrict flavivirus replication independently of innate immune activation. Together, our findings broaden the known antiviral repertoire of SAMD9L, establish its essential role in restricting flavivirus replication via translational repression, and highlight its function as a key component of the cellular defenses against flaviviruses in myeloid cells.

Nature Communications - Sensing of cytosolic RNA or DNA can lead to innate responses, but little information is available for RNA/DNA dual sensors. Here the authors find SAMD9 as a potential dual...

In a recent study published in the journal PLOS Biology, researchers in France investigated the cellular function and antiviral role of human SAMD9L and its paralog SAMD9 (short for sterile alpha motif domain-containing proteins 9 and 9-like) in HIV-1…

Poxviruses have life cycles exclusively in the cytoplasm. With many immunoregulatory proteins manipu