Cell Chemical Biology最新文献

In this issue of Cell Chemical Biology, Pang et al.¹ address the question of how effector CD8⁺ T cells acquire stem-like durability. They uncover a redox-driven metabolic program in which NQO1-mediated cycling of lawsone enhances pentose phosphate pathway, remodels mitochondrial function, and connects effector differentiation to sustained antitumor immunity.

Genetics has been a powerful approach in studying the circadian clock, uncovering the first gene Period (Per) as a key regulator. Human mutation in serine 662 (S662) was found in 2001 to cause familial advanced sleep phase (FASP) syndrome with phase advancement and period shortening. We found S662 phosphorylation by casein kinase 1 (CK1) δ and ε, testis-specific serine kinase (TSSK) 1 and 2, and salt inducible kinase (SIK) 1-3, but no phase advancement phenotype after genetic deletion of any of these seven genes. Our biochemical purification revealed microtubule affinity regulating kinase 2 (MARK2) in phosphorylating S662, binding to and stabilizing PER2. Circadian period was shortened in Mark2-deficient cells in an S662-dependent manner. Neuronal specific Mark2 knockout mice showed phase advancement and period shortening. We have discovered MARK2 as a physiologically significant regulator of the clock, and shown the effectiveness of biochemical purification in mechanistic studies of behaviors.

Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8⁺ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8⁺ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.

The capacity to sense mechanical stimuli represents one of the most fundamental characteristics of life, enabling organisms to navigate their environment. Here, we identify the mechano-antiviral response system (MARS), a Piezo1-mediated pathway that confers broad-spectrum antiviral immunity distinct from known innate immune systems. Using enterovirus D68 (EV-D68) as a model, we demonstrate that cellular compression or fluid pressure activates Piezo1-dependent antiviral resistance in non-immune cells. Piezo1 functions as a natural antiviral factor, and its pharmacological activation protects against multiple clinical isolates of EV-D68. Mechanistically, the activation of the biomechanical-Piezo1 axis results in a marked reduction in host cell membrane fluidity, a critical determinant for viral entry. Consequently, MARS restricts the replication of diverse viruses, including rhinovirus and influenza. In vivo studies reveal that Piezo1 agonists or mechanical stimuli alleviate EV-D68-induced neurological damage and lethality. Our findings underscore MARS-mediated membrane remodeling as a non-canonical antiviral strategy, expanding the paradigms of immune stimulation.