The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family ...consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.
New Opportunities in Refractory Alloys Philips, N. R.; Carl, M.; Cunningham, N. J.
Metallurgical and materials transactions. A, Physical metallurgy and materials science,
07/2020, Letnik:
51, Številka:
7
Journal Article
Recenzirano
For decades, the promise of refractory alloys (robust structural materials for use above 1500 K (1200 °C)) has been hampered by concurrent requirements for fabricability
via
ingot metallurgy and ...oxidation resistance. These constraints have thus far proven impossible to meet in a single material. The work herein demonstrates that the advent of economical powder feedstocks and consolidation methods, such as additive manufacturing (AM), effectively removes the constraints preventing widespread utilization of high-strength refractory alloys into aerospace, defense, and space access applications. High-purity, spherical refractory-alloy powders (
e.g.
the Nb-10Hf-1Ti alloy ATI C103™) were made
via
both atomization and plasma spheroidization and consolidated using a variety of methods. Consolidated material shows comparable and sometimes superior high temperature performance to equivalent wrought material. The availability of cost-effective powder synthesis techniques enables the elimination of critical barriers in fabrication: namely the requirement for hot and cold working. The availability of AM and hot isostatic pressing expands the design space for high-strength refractory alloys and makes the adoption of new paradigms in alloy design, such as refractory complex concentrated alloys, plausible. Going forward, the most difficult challenge, oxidation, can be tackled with the new approaches that are now available.
Insulin gene coding sequence mutations are known to cause mutant INS-gene-induced diabetes of youth (MIDY), yet the cellular pathways needed to prevent misfolded proinsulin accumulation remain ...incompletely understood. Here, we report that Akita mutant proinsulin forms detergent-insoluble aggregates that entrap wild-type (WT) proinsulin in the endoplasmic reticulum (ER), thereby blocking insulin production. Two distinct quality-control mechanisms operate together to combat this insult: the ER luminal chaperone Grp170 prevents proinsulin aggregation, while the ER membrane morphogenic protein reticulon-3 (RTN3) disposes of aggregates via ER-coupled autophagy (ER-phagy). We show that enhanced RTN-dependent clearance of aggregated Akita proinsulin helps to restore ER export of WT proinsulin, which can promote WT insulin production, potentially alleviating MIDY. We also find that RTN3 participates in the clearance of other mutant prohormone aggregates. Together, these results identify a series of substrates of RTN3-mediated ER-phagy, highlighting RTN3 in the disposal of pathogenic prohormone aggregates.
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•Akita mutant proinsulin forms detergent-insoluble aggregates•Akita aggregate formation is actively prevented by the ER-resident chaperone Grp170•RTN3-dependent ER-phagy clears Akita and other prohormone aggregates•RTN-mediated clearance of Akita aggregates partially restores WT proinsulin secretion
To clarify how prohormone aggregates in the endoplasmic reticulum (ER) are removed, Cunningham et al. identified two distinct mechanisms. Specifically, the ER luminal chaperone Grp170 acts to prevent aggregate formation, while an RTN3-dependent ER-phagy pathway clears the buildup of the aggregates via an ER-to-lysosome degradation route.
The Hippo signaling pathway is responsible for regulating the function of TEAD family transcription factors in metazoans. TEADs, with their co-activators YAP/TAZ, are critical for controlling cell ...differentiation and organ size through their transcriptional activation of genes involved in cell growth and proliferation. Dysregulation of the Hippo pathway has been implicated in multiple forms of cancer. Here, we identify a novel form of regulation of TEAD family proteins. We show that human TEADs are palmitoylated at a universally conserved cysteine, and report the crystal structures of the human TEAD2 and TEAD3 YAP-binding domains in their palmitoylated forms. These structures show a palmitate bound within a highly conserved hydrophobic cavity at each protein's core. Our findings also demonstrate that this modification is required for proper TEAD folding and stability, indicating a potential new avenue for pharmacologically regulating the Hippo pathway through the modulation of TEAD palmitoylation.
•TEAD proteins are palmitoylated in human cells•Palmitoylation is required for TEAD stability•TEAD proteins do not stably associate with the nuclear envelope
Noland et al. report that TEAD transcription factors are palmitoylated. Structures of the palmitoylated YAP-binding domains of TEAD2 and TEAD3 are presented. Palmitoylation is required for TEAD stability, highlighting a novel form of regulation of the Hippo signaling pathway.
Multiple lines of evidence indicate that mitochondrial dysfunction is central to Parkinson's disease. Here we investigate the mechanism by which parkin, an E3 ubiquitin ligase, and USP30, a ...mitochondrion-localized deubiquitylase, regulate mitophagy. We find that mitochondrial damage stimulates parkin to assemble Lys 6, Lys 11 and Lys 63 chains on mitochondria, and that USP30 is a ubiquitin-specific deubiquitylase with a strong preference for cleaving Lys 6- and Lys 11-linked multimers. Using mass spectrometry, we show that recombinant USP30 preferentially removes these linkage types from intact ubiquitylated mitochondria and counteracts parkin-mediated ubiquitin chain formation in cells. These results, combined with a series of chimaera and localization studies, afford insights into the mechanism by which a balance of ubiquitylation and deubiquitylation regulates mitochondrial homeostasis, and suggest a general mechanism for organelle autophagy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Radio continuum observations using the Australia telescope compact array at 5.5, 9.0, 17.0 and 22.8 GHz have detected free–free emission associated with 45 of 49 massive young stellar objects and ...H ii regions. Of these, 26 sources are classified as ionized jets (12 of which are candidates), 2 as ambiguous jets or disc winds, 1 as a disc-wind, 14 as H ii regions and 2 were unable to be categorized. Classification as ionized jets is based upon morphology, radio flux and spectral index, in conjunction with previous observational results at other wavelengths. Radio luminosity and momentum are found to scale with bolometric luminosity in the same way as low-mass jets, indicating a common mechanism for jet production across all masses. In 13 of the jets, we see associated non-thermal/optically thin lobes resulting from shocks either internal to the jet and/or at working surfaces. 10 jets display non-thermal (synchrotron emission) spectra in their lobes, with an average spectral index of α = −0.55 consistent with Fermi acceleration in shocks. This shows that magnetic fields are present, in agreement with models of jet formation incorporating magnetic fields. Since the production of collimated radio jets is associated with accretion processes, the results presented in this paper support the picture of disc-mediated accretion for the formation of massive stars with an upper limit on the jet phase lasting approximately 6.5 × 104 yr. Typical mass-loss rates in the jet are found to be 1.4 × 10−5 M⊙ yr−1 with associated momentum rates of the order of (1–2) × 10−2 M⊙ km s−1 yr−1.
Context.
The mass segregation of stellar clusters could be primordial rather than dynamical. Despite the abundance of studies of mass segregation for stellar clusters, those for stellar progenitors ...are still scarce, so the question concerning the origin and evolution of mass segregation is still open.
Aims.
Our goal is to characterize the structure of the NGC 2264 molecular cloud and compare the populations of clumps and young stellar objects (YSOs) in this region whose rich YSO population has shown evidence of sequential star formation.
Methods.
We separated the
Herschel
column density map of NGC 2264 into three subregions and compared their cloud power spectra using a multiscale segmentation technique. We extracted compact cloud fragments from the column density image, measured their basic properties, and studied their spatial and mass distributions.
Results.
In the whole NGC 2264 cloud, we identified a population of 256 clumps with typical sizes of ~0.1 pc and masses ranging from 0.08
M
⊙
to 53
M
⊙
. Although clumps have been detected all over the cloud, most of the massive, bound clumps are concentrated in the central subregion of NGC 2264. The local surface density and the mass segregation ratio indicate a strong degree of mass segregation for the 15 most massive clumps, with a median Σ
6
three times that of the whole clumps population and Λ
MSR
≃ 8. We show that this cluster of massive clumps is forming within a high-density cloud ridge, which is formed and probably still fed by the high concentration of gas observed on larger scales in the central subregion. The time sequence obtained from the combined study of the clump and YSO populations in NGC 2264 suggests that the star formation started in the northern subregion, that it is now actively developing at the center, and will soon start in the southern subregion.
Conclusions.
Taken together, the cloud structure and the clump and YSO populations in NGC 2264 argue for a dynamical scenario of star formation. The cloud could first undergo global collapse, driving most clumps to centrally concentrated ridges. After their main accretion phase, some YSOs, and probably the most massive, would stay clustered while others would be dispersed from their birth sites. We propose that the mass segregation observed in some star clusters is inherited from that of clumps, originating from the mass assembly phase of molecular clouds.
The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 ...proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7–A7, B19–A20, and A6–A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide‐linked protein complexes, is a natural by‐product of proinsulin biosynthesis, as is the case for many proteins. The steady‐state level of misfolded proinsulin—a potential ER stressor—is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene–induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.
Context.
The infrared dark cloud (IRDC) SDC335.579-0.292 (hereafter, SDC335) is a massive (~5000
M
⊙
) star-forming cloud which has been found to be globally collapsing towards one of the most ...massive star forming cores in the Galaxy, which is located at its centre. SDC335 is known to host three high-mass protostellar objects at early stages of their evolution and archival ALMA Cycle 0 data (at ~5′′ resolution) indicate the presence of at least one molecular outflow in the region detected in HNC. Observations of molecular outflows from massive protostellar objects allow us to estimate the accretion rates of the protostars as well as to assess the disruptive impact that stars have on their natal clouds during their formation.
Aims.
The aim of this work is to identify and analyse the properties of the protostellar-driven molecular outflows within SDC335 and use these outflows to help refine the properties of the young massive protostars in this cloud.
Methods.
We imaged the molecular outflows in SDC335 using new data from the Australia Telescope Compact Array of SiO and Class I CH
3
OH maser emission (at a resolution of ~3′′) alongside observations of four CO transitions made with the Atacama Pathfinder EXperiment and archival Atacama Large Millimeter/submillimeter Array (ALMA) CO,
13
CO (~1′′), and HNC data. We introduced a generalised argument to constrain outflow inclination angles based on observed outflow properties. We then used the properties of each outflow to infer the accretion rates on the protostellar sources driving them. These accretion properties allowed us to deduce the evolutionary characteristics of the sources. Shock-tracing SiO emission and CH
3
OH Class I maser emission allowed us to locate regions of interaction between the outflows and material infalling to the central region via the filamentary arms of SDC335.
Results.
We identify three molecular outflows in SDC335 – one associated with each of the known compact H
II
regions in the IRDC. These outflows have velocity ranges of ~10 km s
−1
and temperatures of ~60 K. The two most massive sources (separated by ~9000 AU) have outflows with axes which are, in projection, perpendicular. A well-collimated jet-like structure with a velocity gradient of ~155 km s
−1
pc
−1
is detected in the lobes of one of the outflows. The outflow properties show that the SDC335 protostars are in the early stages (Class 0) of their evolution, with the potential to form stars in excess of 50
M
⊙
. The measured total accretion rate, inferred from the outflows, onto the protostars is 1.4(±0.1) × 10
−3
M
⊙
yr
−1
, which is comparable to the total mass infall rate toward the cloud centre on parsec scales of 2.5(±1.0) × 10
−3
M
⊙
yr
−1
, suggesting a near-continuous flow of material from cloud to core scales. Finally, we identify multiple regions where the outflows interact with the infalling material in the cloud’s six filamentary arms, creating shocked regions and pumping Class I methanol maser emission. These regions provide useful case studies for future investigations of the disruptive effect of young massive stars on their natal clouds.
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