Cell Research最新文献

Oncogenic mutations in EGFR often result in EGF-independent constitutive activation and aberrant trafficking and are associated with several human malignancies, including non-small cell lung cancer. A major consequence of EGFR mutations is the activation of the mechanistic target of rapamycin complex 1 (mTORC1), which requires EGFR kinase activity and downstream PI3K/AKT signaling, resulting in increased cell proliferation. However, recent studies have elucidated kinase-independent roles of EGFR in cell survival and cancer progression. Here, we report a cis mTORC1 activation function of EGFR that is independent of its kinase activity. Our results reveal that lysosomal localization of EGFR is critical to mTORC1 activation, where EGFR physically binds Rheb, acting as a guanine exchange factor (GEF) for Rheb, with its Glu804 serving as a potential glutamic finger. Genetic knock-in of EGFR-E804K in cells reduces the level of GTP-bound Rheb, and significantly suppresses mTORC1 activation, cell proliferation and tumor growth. Different tyrosine kinase inhibitors exhibit distinct effects on EGFR-induced mTORC1 activation, with afatinib, which additionally blocks EGFR’s GEF activity, causing a much greater suppression of mTORC1 activation and cell growth, and erlotinib, which targets only kinase activity, resulting in only a slight decrease. Moreover, a novel small molecule, BIEGi-1, was designed to target both the Rheb-GEF and kinase activities of EGFR, and shows a strong inhibitory effect on the viability of cells harboring EGFR mutants. These findings unveil a fundamental event in cell growth and suggest a promising strategy against cancers with EGFR mutations.

Activation of the innate immune sensor protein NLRP3 leads to the assembly of a multiprotein complex called the inflammasome, causing cell death and inflammation. In a recent paper in Cell Research, Zou et al. now provide evidence that palmitoylation of NLRP3 promotes its liquid–liquid phase separation, driving inflammasome activation.

Pyroptosis is a highly immunogenic cell death due to the release of damage-associated molecular patterns and pro-inflammatory cytokines such as IL-1β and IL-18. A recent study published in Cell by Wright and colleagues uncovered a novel mechanism in which extracellular vesicles released from pyroptotic cells serve as carriers of functional gasdermin D pores to propagate pyroptosis to bystander cells, providing valuable insights into the process of bystander cell death and opening up potential therapeutic avenues.

Biased allosteric modulators provide great therapeutic potential by selectively directing signal bias in the presence of endogenous ligand under (patho)physiological conditions. In a recent Cell Research paper, Sun et al. revealed the structural mechanisms underlying the biased allosteric modulation exerted by SBI-533 directly at the neurotensin receptor 1–β-arrestin1 interface.

Intron removal from pre-mRNAs is one of the key steps in gene expression, but how it is achieved with high fidelity remains a subject of active research. Recent structural studies provide new insights into the spliceosome-mediated splice site proofreading mechanism.

In animals, AGO-clade Argonaute proteins utilize small interfering RNAs (siRNAs) as guides to recognize target with complete complementarity, resulting in target RNA cleavage that is a critical step for target silencing. These proteins feature a constricted nucleic acid-binding channel that limits base pairing between the guide and target beyond the seed region. How the AGO–siRNA complexes overcome this structural limitation and achieve efficient target cleavage remains unclear. We performed cryo-electron microscopy of human AGO–siRNA complexes bound to target RNAs of increasing lengths to examine the conformational changes associated with target recognition and cleavage. Initially, conformational transition propagates from the opening of the PAZ domain and extends through a repositioning of the PIWI–L1–N domain toward the binding channel, facilitating the capture of siRNA–target duplex. Subsequent extension of base pairing drives the downward movement of the PIWI–L1–N domain to enable catalytic activation. Finally, further base pairing toward the 3′ end of siRNA destabilizes the PAZ–N domain, resulting in a “uni-lobed” architecture, which might facilitate the multi-turnover action of the AGO–siRNA enzyme complex. In contrast to PIWI-clade Argonautes, the “uni-lobed” structure of the AGO complex makes multiple contacts with the target in the central region of the siRNA–target duplex, positioning it within the catalytic site. Our findings shed light on the stepwise mechanisms by which the AGO–siRNA complex executes target RNA cleavage and offer insights into the distinct operational modalities of AGO and PIWI proteins in achieving such cleavage.

Proteins within cells must navigate complex intracellular environments to co-localize with partners and regulate functional cellular organization. In a recentScience paper, Kilgore et al. report the development of ProtGPS, a machine learning-trained predictor of protein localization within biomolecular condensates in cells that can be used to predict the ability of disease-linked mutations to dysregulate protein localization to biomolecular condensates.

Although CDK4/6 inhibitors have revolutionized the management of patients with locally advanced/metastatic HR⁺HER2⁻ breast cancer, hematological side effects, notably neutropenia, have been challenging to circumvent. A highly selective CDK4 inhibitor has recently been shown to cause limited hematological toxicity in preclinical breast cancer models, hence enabling dose escalation in support of superior tumor control.

In a recent study, Ding et al. investigated the role of hnRNPK phase separation in mammalian dosage compensation. The study stands out by linking biophysical and biochemical measurements with genetic and cell biological experimentation, providing wide-ranging evidence for specific mechanistic aspects of X chromosome inactivation, while expanding the potential repertoire for phase separation in biology.

Pyroptosis is a type of programmed necrosis triggered by the detection of pathogens or endogenous danger signals in the cytosol. Pyroptotic cells exhibit a swollen, enlarged morphology and ultimately undergo lysis, releasing their cytosolic contents - such as proteins, metabolites, and nucleic acids - into the extracellular space. These molecules can function as danger-associated molecular patterns (DAMPs), triggering inflammation when detected by neighboring cells. Mechanistically, pyroptosis is initiated by members of the gasdermin protein family, which were identified a decade ago as pore-forming executors of cell death. Mammalian gasdermins consist of a cytotoxic N-terminal domain, a flexible linker, and a C-terminal regulatory domain that binds to and inhibits the N-terminus. Proteolytic cleavage within the linker releases the N-terminal domain, enabling it to target various cellular membranes, including nuclear, mitochondrial, and plasma membranes, where it forms large transmembrane pores. Gasdermin pores in the plasma membrane disrupt the electrochemical gradient, leading to water influx and cell swelling. Their formation also activates the membrane protein ninjurin-1 (NINJ1), which oligomerizes to drive complete plasma membrane rupture and the release of large DAMPs. Since their discovery as pore-forming proteins, gasdermins have been linked to pyroptosis not only in host defense but also in various pathological conditions. This review explores the history of pyroptosis, recent insights into gasdermin activation, the cellular consequences of pore formation, and the physiological roles of pyroptosis.