Chantharath, A. | bioRxiv Science

bioRxiv2026

TAK1 integrates the NLRP1 inflammasome into the innate immune response to double-stranded RNA

Innate immune recognition of double-stranded RNA (dsRNA) by germline-encoded receptors initiates antiviral defenses, including type I interferon (IFN) production. The inflammasome-forming sensor NLRP1 binds and is activated by dsRNA in a mitogen-activated protein kinase (MAPK) p38-dependent manner. How dsRNA initiates these events to induce NLRP1 inflammasome activation is unclear. Here we demonstrate that both exogenous and cellular dsRNA triggers NLRP1 inflammasome activation downstream of RIG-I/MDA5-MAVS and/or TLR3-TRIF signaling but is independent of type I IFN. In immortalized and primary human keratinocytes, we find that NLRP1 inflammasome activation by dsRNA, including during viral infection, requires the MAPK kinase kinase TAK1. Mechanistically, TAK1-dependent phosphorylation of the NLRP1 N-terminal disordered region is necessary and sufficient for inflammasome activation. Collectively, we reveal TAK1 as a novel activator of the NLRP1 inflammasome, functioning as a critical signaling hub linking NLRP1 to inflammatory responses in the context of viral infection and autoimmunity.

immunology↗

bioRxiv2025

Ancient convergence with prokaryote defense and recent adaptations to lentiviruses in primates characterize the ancestral immune factors SAMD9s

Human SAMD9 and SAMD9L are duplicated genes that encode innate immune proteins restricting poxviruses and lentiviruses, such as HIV, and implicated in life-threatening genetic diseases and cancer. Here, we combined structural similarity searches, phylogenetics and population genomics with experimental assays of SAMD9/9L functions to resolve the evolutionary and functional dynamics of these immune proteins, spanning from prokaryotes to primates. We discovered structural analogs of SAMD9/9L in the anti-bacteriophage defense system Avs, resulting from convergent evolution. Further, the predicted nuclease active site was conserved in bacterial analogs and was essential for cell death functions, suggesting a fundamental role in defense across different life kingdoms. Despite this ancestral immunity, we identified genomic signatures of evolutionary arms-races in mammals, with remarkable gene copy number variations targeted by natural selection. We further unveiled that the absence of SAMD9 in bonobos corresponds to a recent gene loss still segregating in the population. Finally, we found that chimp and bonobo SAMD9Ls have enhanced anti-HIV-1 functions, and that bonobo-specific SAMD9L polymorphisms confer increased anti-HIV-1 activity to human SAMD9L without compromising its effect on cell translation. These SAMD9/9L adaptations likely resulted from strong viral selective pressures, including by primate lentiviruses, and could contribute to lentiviral resistance in bonobos. Altogether, this study elucidates the interplay between ancient immune convergence across kingdoms and species-specific adaptations within the Avs9 and SAMD9/9L antiviral shared immunity. Significance statementThe SAMD9 gene family encodes antiviral factors of poxviruses and lentiviruses/HIV and is implicated in genetic diseases. Here, we found strong structural similarity with proteins from the Avs anti-bacteriophage system and uncovered ancient functional convergence in immune strategies between prokaryotes and metazoans. Within mammals, and more importantly in primates, we describe a highly dynamic evolutionary history of the SAMD9 gene family that underwent adaptive episodic gene losses. Unlike humans and chimps, some bonobos lack the SAMD9 gene entirely. Bonobos and chimps also possess unique variants of SAMD9L enhancing anti-HIV-1 activity without compromising cell functions, suggesting super-restrictors. This could also participate in shaping SIVcpz evolution and contribute to the absence of lentivirus-infected bonobos. Overall, the seeming dichotomy between the ancient evolutionary convergence in different kingdoms and recent functional adaptation within primates highlights the arms-races between key immune defense systems and viruses. This study paves the way for evolutionary medicine, where evolutionary-based discoveries may have application to human health, providing a deeper understanding of how the immune system adapts to fight viral infections over billion years of evolution.

evolutionary biology↗

bioRxiv2025

Microtubule remodeling by the innate immune factor Trim69 compromises dynein-dependent migration of HIV virion cores towards the nucleus

Like many viruses, HIV relies on the microtubule (MT) cytoskeleton for successful infection. MT-associated proteins (MAPs) regulate MT functions and thus bear the potential to modulate viral infection. However, while several MAPs are known to exert pro-viral effects on HIV, little is known about antiviral ones. We previously described the Tripartite motif protein 69 (Trim69) as an innate immune factor that remodels MTs, leading to inhibition of a broad spectrum of viruses, including HIV. Through in silico modeling, TIRF microscopy and cell-based assays, we determine that Trim69 binding to MTs is determined by a basic surface in its SPRY domain that interacts with the C-terminal tails of tubulins. This surface is conserved among mammalian Trim69s and is critical for its functions. We demonstrate that by binding and remodeling MTs, Trim69 inhibits the docking and the migration of virion cores on MTs by promoting the stalling of the dynein/dynactin motor complexes. Altogether, these findings shed light on a novel mechanism of viral defense that involves an innate immune regulation of the MT cytoskeleton.

cell biology↗