The ability to sense cellular temperature and induce physiological changes is pivotal for plants to cope with warming climate. Biomolecular condensation is emerging as a thermo-sensing mechanism, but the underlying molec...The ability to sense cellular temperature and induce physiological changes is pivotal for plants to cope with warming climate. Biomolecular condensation is emerging as a thermo-sensing mechanism, but the underlying molecular basis remains elusive. Here we show that an intrinsically disordered protein FUST1 senses heat via its condensation in Arabidopsis thaliana. Heat-dependent condensation of FUST1 is primarily determined by its prion-like domain (PrLD). All-atom molecular dynamics simulation and experimental validation reveal that PrLD encodes a thermo-switch, experiencing lock-to-open conformational changes that control the intermolecular contacts. FUST1 interacts with integral stress granule (SG) components and localizes in the SGs. Importantly, FUST1 condensation is autonomous and precedes condensation of several known SG markers and is indispensable for SG assembly. Loss of FUST1 significantly delays SG assembly and impairs both basal and acquired heat tolerance. These findings illuminate the molecular basis for thermo-sensing by biomolecular condensation and shed light on the molecular mechanism of heat stress granule assembly.
Cytoplasmic DNA emerges as a consequence of genomic instability. However, its potential role in disease diagnosis has yet to be fully explored. Here we analyzed DNA remnants in mature red blood cells (rbcDNA) from both h...Cytoplasmic DNA emerges as a consequence of genomic instability. However, its potential role in disease diagnosis has yet to be fully explored. Here we analyzed DNA remnants in mature red blood cells (rbcDNA) from both healthy individuals and cancer patients. Our study unveiled distinct genomic profiles in rbcDNA from cancer patients with early-stage solid tumors compared to those of healthy donors. Significant changes in read counts at specific genomic regions within rbcDNA were identified in patients, which were termed tumor-associated rbcDNA features. These features demonstrated potential for highly accurate early-stage cancer detection, proposing a novel approach for cancer detection. Moreover, tumor-associated rbcDNA features were observed in tumor mouse models, with some features being conserved between mice and humans. Chronic, but not transient, up-regulation of interleukin-18 is essential for the development of these features by promoting DNA damage in bone marrow hematopoietic cells through the up-regulation of NR4A1. These results underscore the remote regulation of chromosomal stability in hematopoietic cells by solid tumors and propose tumor-associated rbcDNA features as a promising strategy for early cancer detection.
He X, Wang QX, Wei D
… +17 more, Lin Y, Zhang X, Wu Y, Qian X, Lin Z, Xiao B, Wu Q, Wang Z, Zhou F, Wei Z, Wang J, Gong R, Zhang R, Zhang Q, Ding K, Gao S, Kang T
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 o...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.
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 by Wright and colleagues uncov...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 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.
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....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.