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doi: 10.1038/s41556-022-00963-3pmid: 35941366
NADPH levels serve as a biomarker of sensitivity to ferroptosis, but the regulators that detect cellular NADPH levels and modulate downstream ferroptosis responses are unknown. A study now identifies MARCHF6 in the ubiquitin system as an NADPH sensor that suppresses ferroptosis.
Delaunay, Sylvain; Frye, Michaela
doi: 10.1038/s41556-022-00972-2pmid: 35927452
Aberrant subcellular localization of proteins contributes to the pathogenesis of cancer. A study now reports that the mis-localization of METTL3, a nuclear N6-adenosine methyltransferase, to the cytoplasm promotes gastric cancer by enhancing mRNA translation of a subset of oncogenes, independently of the N6-methyladenosine (m6A) modification.
Beytagh, Mary Clare; Weiss, William A.
doi: 10.1038/s41556-022-00967-zpmid: 35915160
EGFR is an oncogene that is frequently amplified in glioblastoma. A new study suggests a tumour-suppressive role of EGFR in EGFR-amplified glioblastoma regulated by ligand abundance. Increased EGFR ligand in EGFR-amplified glioblastoma suppresses invasion by upregulating BIN3 and inhibiting activation of Rho GTPases.
Li, Zheqi; Seehawer, Marco; Polyak, Kornelia
doi: 10.1038/s41556-022-00969-xpmid: 35941364
Intratumour heterogeneity (ITH) is a hallmark of cancer that drives tumour evolution and disease progression. Technological and computational advances have enabled us to assess ITH at unprecedented depths, yet this accumulating knowledge has not had a substantial clinical impact. This is in part due to a limited understanding of the functional relevance of ITH and the inadequacy of preclinical experimental models to reproduce it. Here, we discuss progress made in these areas and illuminate future directions.
Hao, Xue; Shiromoto, Yusuke; Sakurai, Masayuki; Towers, Martina; Zhang, Qiang; Wu, Shuai; Havas, Aaron; Wang, Lu; Berger, Shelley; Adams, Peter D.; Tian, Bin; Nishikura, Kazuko; Kossenkov, Andrew V.; Liu, Pingyu; Zhang, Rugang
Chandrakanthan, Vashe; Rorimpandey, Prunella; Zanini, Fabio; Chacon, Diego; Olivier, Jake; Joshi, Swapna; Kang, Young Chan; Knezevic, Kathy; Huang, Yizhou; Qiao, Qiao; Oliver, Rema A.; Unnikrishnan, Ashwin; Carter, Daniel R.; Lee, Brendan; Brownlee, Chris; Power, Carl; Brink, Robert; Mendez-Ferrer, Simon; Enikolopov, Grigori;
Mylvaganam, Sivakami; Plumb, Jonathan; Yusuf, Bushra; Li, Ren; Lu, Chien-Yi; Robinson, Lisa A.; Freeman, Spencer A.; Grinstein, Sergio
doi: 10.1038/s41556-022-00953-5pmid: 35817960
Physiological blood flow induces the secretion of vasoactive compounds, notably nitric oxide, and promotes endothelial cell elongation and reorientation parallel to the direction of applied shear. How shear is sensed and relayed to intracellular effectors is incompletely understood. Here, we demonstrate that an apical spectrin network is essential to convey the force imposed by shear to endothelial mechanosensors. By anchoring CD44, spectrins modulate the cell surface density of hyaluronan and sense and translate shear into changes in plasma membrane tension. Spectrins also regulate the stability of apical caveolae, where the mechanosensitive PIEZO1 channels are thought to reside. Accordingly, shear-induced PIEZO1 activation and the associated calcium influx were absent in spectrin-deficient cells. As a result, cell realignment and flow-induced endothelial nitric oxide synthase stimulation were similarly dependent on spectrin. We conclude that the apical spectrin network is not only required for shear sensing but also transmits and distributes the resulting tensile forces to mechanosensors that elicit protective and vasoactive responses.
Showing 1 to 10 of 17 Articles
Imaging technologies drive discovery in cell biology. Innovations in microscopy hardware, imaging methods and computational analysis of large-scale, complex datasets can increase imaging resolution, definition and allow access to new biology. We asked experts at the leading edge of biological imaging what they are most excited about when it comes to microscopy in cell biology and what challenges need to be overcome to reach these goals.
doi: 10.1038/s41556-022-00959-zpmid: 35851616
Cellular senescence plays a causal role in ageing and, in mice, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders1,2. Adenosine deaminases acting on RNA (ADARs) are RNA-editing enzymes that are also implicated as important regulators of human ageing, and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms3,4. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through p16INK4a upregulation. The ADAR1 downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a-dependent and independent of its RNA-editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA-binding protein that increases the half-life and steady-state levels of its target mRNAs. SIRT1 in turn antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4a upregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing-independent role for ADAR1 in the regulation of senescence by post-transcriptionally controlling p16INK4a expression.
doi: 10.1038/s41556-022-00955-3pmid: 35902769
Mouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition. We investigated whether mesenchymal stem cells, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta–gonad–mesonephros and contribute to the development of the dorsal aorta and endothelial-to-haematopoietic transition. Here we show that mesoderm-derived PDGFRA+ stromal cells (Mesp1der PSCs) contribute to the haemogenic endothelium of the dorsal aorta and populate the E10.5–E11.5 aorta–gonad–mesonephros but by E13.5 were replaced by neural-crest-derived PSCs (Wnt1der PSCs). Co-aggregating non-haemogenic endothelial cells with Mesp1der PSCs but not Wnt1der PSCs resulted in activation of a haematopoietic transcriptional programme in endothelial cells and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA or BMP, WNT and NOTCH signalling interrupted this reprogramming event. Together, aorta–gonad–mesonephros Mesp1der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.