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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 8, 2025

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

Язык: Английский

The ELF3-TRIM22-MAVS signaling axis regulates type I interferon and antiviral responses

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

ABSTRACT Activation of the innate immune response is essential for host cells to restrict dissemination invading viruses and other pathogens. Proteins belonging tripartite motif (TRIM) family are key effectors in antiviral immunity. Among these, TRIM22, a RING-type E3 ubiquitin ligase, has been recognized as significant regulator pathogenesis various diseases. In present study, we identified TRIM22 critical modulator mitochondrial signaling protein (MAVS) activation. Loss function led reduced production type I interferons (IFNs) viral infection such influenza A virus (IAV) or vesicular stomatitis (VSV), thereby facilitating replication. Mechanistically, was found enhance retinoic acid-inducible gene (RIG-I)-mediated through catalysis Lys63-linked polyubiquitination MAVS, which, turn, activated TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) pathway, driving IFN-β production. Additionally, shown inhibit assembly MAVS-NLRX1 inhibitory complex, further amplifying responses. Our findings also demonstrated that RNA upregulated expression via nuclear translocation ELF3, transcription activates expression. This loop underscores role modulating IFN providing insights into host’s defense mechanisms. research highlights potential targeting ELF3-TRIM22-MAVS axis therapeutic strategy enhancing immunity preventing infections. IMPORTANCE Interferon (IFN)-mediated responses crucial against foreign pathogens regulated by pathways. The family, its multifaceted roles regulation defense, plays part this process. our explored important helped regulate We enhances (MAVS), which producing interferons. Interestingly, discovered increases after an infection, due moved nucleus activate transcription. created feedback strengthens pathway. By uncovering these mechanisms, aimed understanding how system works provide could lead innovative therapies.

Язык: Английский

TRIM proteins: A ‘swiss army knife’ of antiviral immunity

PLoS Pathogens, Год журнала: 2025, Номер 21(5), С. e1013147 - e1013147

Опубликована: Май 12, 2025

With their modular structure and E3 ubiquitin ligase activity, Tripartite motif (TRIM) proteins interact with a wide range of cellular viral substrates. This review summarizes how they have emerged as key players in the antiviral response. Shortly, TRIM were shown (i) to enhance pro-inflammatory cytokines production by interacting pattern recognition receptors downstream components immune signaling pathways, (ii) interfere trafficking cytoskeleton, (iii) exhibit direct effects targeting for proteasomal degradation or inducing autophagy. combination actions underscores TRIMs potent innate defense system, but also makes them vulnerable evasion strategies.

Язык: Английский