Cell insight最新文献

The stimulator of interferon genes (STING) plays a pivotal role in orchestrating innate immunity, and dysregulated activity of STING has been implicated in the pathogenesis of autoimmune diseases. Recent findings suggest that bacterial infection activates STING, relieving ER stress, and triggers non-canonical autophagy by spatially regulating STX17. Despite these insights, the precise mechanism governing the dynamics of autophagosome fusion elicited by STING remains unclear. In this study, we demonstrate that dynamic STING activation guides the autophagy flux, mirroring the trajectory of canonical autophagy adaptors. STING engages in a physical interaction with STX17, and agonist-induced phosphorylation or degradation alleviates STING's inhibitory effects on the assembly of the STX17-SNAP29-VAMP8 complex. Consistent with these findings, degradation-deficient mutants hinder autophagy flux by impeding STX17-mediated autophagosome-lysosome fusion. Moreover, STING mutants associated with lupus disrupt the assembly of the STX17-SNAP29-VAMP8 complex and autophagy process, which lead to persistent STING activation and elevated IFN-β production. Our results highlight that the intracellular trajectory of STING, coupled with autophagy flux, guides the assembly and membrane fusion of the STX17-SNAP29-VAMP8 complex, ensuring the accurate regulation of innate immunity.

Angiotensin-converting enzyme 2 (ACE2) was recognized as an entry receptor shared by coronaviruses from Sarbecovirus and Setracovirus subgenera, including three human coronaviruses: SARS-CoV, SARS-CoV-2, and NL63. We recently disclosed that NeoCoV and three other merbecoviruses (PDF-2180, MOW15-22, PnNL 2018B), which are MERS-CoV relatives found in African and European bats, also utilize ACE2 as their functional receptors through unique receptor binding mechanisms. This unexpected receptor usage assumes significance, particularly in light of the prior recognition of Dipeptidyl peptidase-4 (DPP4) as the only known protein receptor for merbecoviruses. In contrast to other ACE2-using coronaviruses, NeoCoV and PDF-2180 engage a distinct and relatively compact binding surface on ACE2, facilitated by protein-glycan interactions, which is demonstrated by the Cryo-EM structures of the receptor binding domains (RBDs) of these viruses in complex with a bat ACE2 orthologue. These findings further support the hypothesis that phylogenetically distant coronaviruses, characterized by distinct RBD structures, can independently evolve to acquire ACE2 affinity during inter-species transmission and adaptive evolution. To date, these viruses have exhibited limited efficiency in entering human cells, although single mutations like T510F in NeoCoV can overcome the incompatibility with human ACE2. In this review, we present a comprehensive overview of ACE2-using merbecoviruses, summarize our current knowledge regarding receptor usage and host tropism determination, and deliberate on potential strategies for prevention and intervention, with the goal of mitigating potential future outbreaks caused by spillover of these viruses.

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 μM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.

The global outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatened human health and public safety. The development of anti-SARS-CoV-2 therapies have been essential to curb the spread of SARS-CoV-2. Particularly, antivirals targeting viral entry have become an attractive target for the development of anti-SARS-CoV-2 therapies. In this review, we elucidate the mechanism of SARS-CoV-2 viral entry and summarize the development of antiviral inhibitors targeting viral entry. Moreover, we speculate upon future directions toward more potent inhibitors of SARS-CoV-2 entry. This study is expected to provide novel insights for the efficient discovery of promising candidate drugs against the entry of SARS-CoV-2, and contribute to the development of broad-spectrum anti-coronavirus drugs.

Brucella, an adept intracellular pathogen, causes brucellosis, a zoonotic disease leading to significant global impacts on animal welfare and the economy. Regrettably, there is currently no approved and effective vaccine for human use. The ability of Brucella to evade host defenses is essential for establishing chronic infection and ensuring stable intracellular growth. Brucella employs various mechanisms to evade and undermine the innate and adaptive immune responses of the host through modulating the activation of pattern recognition receptors (PRRs), inflammatory responses, or the activation of immune cells like dendritic cells (DCs) to inhibit antigen presentation. Moreover, it regulates multiple cellular processes such as apoptosis, pyroptosis, and autophagy to establish persistent infection within host cells. This review summarizes the recently discovered mechanisms employed by Brucella to subvert host immune responses and research progress on vaccines, with the aim of advancing our understanding of brucellosis and facilitating the development of more effective vaccines and therapeutic approaches against Brucella.

Migrasomes are newly identified vesicular structures that mainly come from the ends and crosspoints of retracting fibers in moving cells. Their creation is closely linked with cell movement and goes through three key steps: Nucleation, Maturation, and Expansion. They eventually get released in an event called migracytosis. Migrasomes have become an interesting focus in cell communication, especially during processes like development. They transport a mix of chemokines, growth factors, and morphogens. Their study can offer fresh perspectives on developmental gradients and improve our understanding of how development works. In the mini-review, we summarize our recent progress on the role of migrasomes in development, with a special focus on how migrasomes contribute to the spatial distribution of signalling molecules.