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TSPAN8+ myofibroblastic cancer–associated fibroblasts promote chemoresistance in patients with breast cancer

TSPAN8+ myofibroblastic cancer–associated fibroblasts promote chemoresistance in patients with breast cancer
science.org - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from science.org Daily Mail and Mail on Sunday newspapers.

San-diego , California , United-states , Shanghai , China , Kyoto , Japan , Coomassie , Ashanti , Ghana , American , Matrigel-corning

The HEAT repeat protein HPO-27 is a lysosome fission factor

Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing1. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission2,3. Little is known about the molecular basis of fission. Here we identify HPO-27, a conserved HEAT repeat protein, as a lysosome scission factor in Caenorhabditis elegans. Loss of HPO-27 impairs lysosome fission and leads to an excessive tubular network that ultimately collapses. HPO-27 and its human homologue MROH1 are recruited to lysosomes by RAB-7 and enriched at scission sites. Super-resolution imaging, negative-staining electron microscopy and in vitro reconstitution assays reveal that HPO-27 and MROH1 self-assemble to mediate the constriction and scission of lysosomal tubules in worms and mammalian cells, respectively, and assemble to sever supported membrane tubes in vitro. Loss of HPO-27 affects lysosomal morphology, integrity and degradation activity, which impairs animal development and longevity. Thus, HPO-27 and MROH1 act as self-assembling scission factors to maintain lysosomal homeostasis and function. The conserved HEAT repeat protein HPO-27 is identified as a lysosome scission factor in Caenorhabditis elegans, and the human homologue MROH1 also serves the same function to maintain lysosomal homeostasis.

Coomassie , Ashanti , Ghana , Texas , United-states , Lysotracker-red , Magic-red , Lysotracker-blue-stained ,

The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation

Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2′3′-cyclic GMP-AMP (cGAMP)1–7. The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA8–15. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin–RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation. The ubiquitin proteasomal system degrades nuclear cGAS in cycling cells.

Fiji , Coomassie , Ashanti , Ghana , Cytiva-akt , Lipofectamine-rnai , Jackson-immunoresearch , Microplates-perkin-elmer , Q-exactive-orbitrap , Phenoplate-perkinelmer , Perkinelmer , Proteome-software

The kinase PLK1 promotes the development of Kras/Tp53-mutant lung adenocarcinoma through transcriptional activation of the receptor RET

The kinase PLK1 promotes the development of Kras/Tp53-mutant lung adenocarcinoma through transcriptional activation of the receptor RET
science.org - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from science.org Daily Mail and Mail on Sunday newspapers.

Coomassie , Ashanti , Ghana , E-immunoblotting-kppc , Consortium-for-the-molecular-classification , Drug-administration , Cancer-genome-atlas , Challenge-consortium , Molecular-classification , Junn-terminal ,

Nuclear export of circular RNA

Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1–5, are formed by back-splicing of precursor mRNAs in the nucleus6–10. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export. Circular RNAs are exported from the nucleus by Ran-GTP, exportin-2 and IGF2BP1 in a mechanism analogous to protein export rather than mRNA export.

Coomassie , Ashanti , Ghana , Agilent-tapestation , Cell-profiler , Total-ran ,

Benue Jukun sues Governor, Speaker, Tor Tiv, others over discriminatory policies

Benue Jukun sues Governor, Speaker, Tor Tiv, others over discriminatory policies
peoplesdailyng.com - get the latest breaking news, showbiz & celebrity photos, sport news & rumours, viral videos and top stories from peoplesdailyng.com Daily Mail and Mail on Sunday newspapers.

Benue , Nigeria-general- , Nigeria , Abuja , Abuja-federal-capital-territory , River-benue , Kogi , Agiri , Oyo , Coomassie , Ashanti , Ghana

Cumulative expression of heterologous XlnR regulatory modules and AraRA731V in Penicillium oxalicum enhances saccharification efficiency of corn stover and corn fiber | Biotechnology for Biofuels and Bioproducts

Penicillium oxalicum engineered strain DB2 and its mutant strains with multiple regulatory modules were constructed. Mutant strain RE-4-2 with two regulatory modules showed a significant increase in the reducing sugar released from corn stover and corn fiber as well as in the conversion of cellulose than DB2. RE-5-2 with three regulatory modules showed a further increase in reducing sugar released from corn stover and the conversion of cellulose on the basis of RE-4-2. RE-4-2-AraRA731V constructed by overexpressing AraRA731V in RE-4-2 showed an increase of 7.2 times and 1.2 times in arabinofuranosidase and xylosidase activities, respectively. Reducing sugar yield and cellulose conversion of corn stover and corn fiber by RE-4-2-AraRA731V were further increased.

China , United-states , Shanghai , Coomassie , Ashanti , Ghana , Endocellulase-cmcase , Microbiological-culture-collection-center , Sangon-biotech , Roche-real-time ,

Coordination of cohesin and DNA replication observed with purified proteins

Two newly duplicated copies of genomic DNA are held together by the ring-shaped cohesin complex to ensure faithful inheritance of the genome during cell division1–3. Cohesin mediates sister chromatid cohesion by topologically entrapping two sister DNAs during DNA replication4,5, but how cohesion is established at the replication fork is poorly understood. Here, we studied the interplay between cohesin and replication by reconstituting a functional replisome using purified proteins. Once DNA is encircled before replication, the cohesin ring accommodates replication in its entirety, from initiation to termination, leading to topological capture of newly synthesized DNA. This suggests that topological cohesin loading is a critical molecular prerequisite to cope with replication. Paradoxically, topological loading per se is highly rate limiting and hardly occurs under the replication-competent physiological salt concentration. This inconsistency is resolved by the replisome-associated cohesion establishment factors Chl1 helicase and Ctf4 (refs. 6,7), which promote cohesin loading specifically during continuing replication. Accordingly, we found that bubble DNA, which mimics the state of DNA unwinding, induces topological cohesin loading and this is further promoted by Chl1. Thus, we propose that cohesin converts the initial electrostatic DNA-binding mode to a topological embrace when it encounters unwound DNA structures driven by enzymatic activities including replication. Together, our results show how cohesin initially responds to replication, and provide a molecular model for the establishment of sister chromatid cohesion. We study the interplay between cohesin and replication by reconstituting a functional replisome using purified proteins, showing how cohesin initially responds to replication and providing a molecular model for the establishment of sister chromatid cohesion.

Coomassie , Ashanti , Ghana , Extended-data , Coomassie-brilliant-blue , Sybr-gold , Wild-type-chl ,

Alternative splicing of latrophilin-3 controls synapse formation

The assembly and specification of synapses in the brain is incompletely understood1–3. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)—a postsynaptic adhesion G-protein-coupled receptor—mediates synapse formation in the hippocampus4 but the mechanisms involved remain unclear. Here we show in mice that LPHN3 organizes synapses through a convergent dual-pathway mechanism: activation of Gαs signalling and recruitment of phase-separated postsynaptic protein scaffolds. We found that cell-type-specific alternative splicing of Lphn3 controls the LPHN3 G-protein-coupling mode, resulting in LPHN3 variants that predominantly signal through Gαs or Gα12/13. CRISPR-mediated manipulation of Lphn3 alternative splicing that shifts LPHN3 from a Gαs- to a Gα12/13-coupled mode impaired synaptic connectivity as severely as the overall deletion of Lphn3, suggesting that Gαs signalling by LPHN3 splice variants mediates synapse formation. Notably, Gαs-coupled, but not Gα12/13-coupled, splice variants of LPHN3 also recruit phase-transitioned postsynaptic protein scaffold condensates, such that these condensates are clustered by binding of presynaptic teneurin and FLRT ligands to LPHN3. Moreover, neuronal activity promotes alternative splicing of the synaptogenic Gαs-coupled variant of LPHN3. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways: Gαs signalling and clustered phase separation of postsynaptic protein scaffolds. Latrophilin-3 organizes synapses through a convergent dual-pathway mechanism in which Gαs signalling is activated and phase-separated postsynaptic protein scaffolds are recruited.

Coomassie , Ashanti , Ghana , Pink-flamindo , Extended-data , Genome-viewer , Total-lphn ,

A new antibiotic traps lipopolysaccharide in its intermembrane transporter

Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet1. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics2–6. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens. A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens.

Coomassie , Ashanti , Ghana , Vitrobot-mark , Durapore-millipore , Perkin-elmer , Anatrace-maumee , Gatan-bioquantum , Fisher-scientific , Global-phasing , Enzo-life-sciences , Gibson