Stress granules and P-bodies are cytosolic biomolecular condensates that dynamically form by the phase separation of RNAs and proteins. They participate in translational control and buffer the ...proteome. Upon stress, global translation halts and mRNAs bound to the translational machinery and other proteins coalesce to form stress granules (SGs). Similarly, translationally stalled mRNAs devoid of translation initiation factors shuttle to P-bodies (PBs). Here, we review the cumulative progress made in defining the protein components that associate with mammalian SGs and PBs. We discuss the composition of SG and PB proteomes, supported by a new user-friendly database (http://rnagranuledb.lunenfeld.ca/) that curates current literature evidence for genes or proteins associated with SGs or PBs. As previously observed, the SG and PB proteomes are biased toward intrinsically disordered regions and have a high propensity to contain primary sequence features favoring phase separation. We also provide an outlook on how the various components of SGs and PBs may cooperate to organize and form membraneless organelles.
Mammalian stress granules and P-bodies are two distinct biomolecular condensates participating in translational control. In this issue, Youn et al. review the protein composition of P-bodies and stress granules and discuss their properties. They also present a curated database of cytosolic RNA granule proteomes in mammalian cells.
Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes ...unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.
The Hippo pathway regulates organ size and tissue homeostasis in response to multiple stimuli, including cell density and mechanotransduction. Pharmacological inhibition of phosphatases can also ...stimulate Hippo signaling in cell culture. We defined the Hippo protein-protein interaction network with and without inhibition of serine and threonine phosphatases by okadaic acid. We identified 749 protein interactions, including 599 previously unrecognized interactions, and demonstrated that several interactions with serine and threonine phosphatases were phosphorylation-dependent. Mutation of the T-loop of MST2 (mammalian STE20-like protein kinase 2), which prevented autophosphorylation, disrupted its association with STRIPAK (striatin-interacting phosphatase and kinase complex). Deletion of the amino-terminal forkhead-associated domain of SLMAP (sarcolemmal membrane-associated protein), a component of the STRIPAK complex, prevented its association with MST1 and MST2. Phosphatase inhibition produced temporally distinct changes in proteins that interacted with MOB1A and MOB1B (Mps one binder kinase activator-like 1A and 1B) and promoted interactions with upstream Hippo pathway proteins, such as MST1 and MST2, and with the trimeric protein phosphatase 6 complex (PP6). Mutation of three basic amino acids that are part of a phospho-serine- and phospho-threonine-binding domain in human MOB1B prevented its interaction with MST1 and PP6 in cells treated with okadaic acid. Collectively, our results indicated that changes in phosphorylation orchestrate interactions between kinases and phosphatases in Hippo signaling, providing a putative mechanism for pathway regulation.
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related ...terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
The glacial land system of western Keewatin region, northern Canada, consists of three significant events: (1) regional emplacement of subglacial sediments, mainly till; (2) landscape erosion with ...development of an integrated, anabranched network of meltwater drainage routes leading to meltwater corridors; and (3) deposition of an extensive array of eskers, and related landforms, within meltwater corridors. Integration of extensive field observations, mapping, and remotely sensed data allow us to link scoured bedrock and till surfaces, truncated drumlins, scour pits, glaciofluvial terraces, boulder lags, and a large-scale network of corridors, as part of regional meltwater erosion events. The network of long (∼100-200 km), relatively wide (∼1-3 km) meltwater corridors record confined subglacial erosion that scoured sediment (and bedrock) prior to glaciofluvial sedimentation (predominately eskers). Despite considerable sediment erosion along meltwater corridors, moraines and other ice-marginal deposits are rarely observed on the western Keewatin landscape. The absence of these features is inconsistent with deglacial models relying on step-wise active retreat of the ice margin. Instead, we propose that deglaciation of the western Keewatin sector of the Laurentide Ice Sheet was predominantly controlled by regional thinning and stagnation. These findings raise fundamental questions about deglacial patterns and processes and thus suggest that further evaluation and revision of existing models of deglacial chronology for this sector of the Laurentide Ice Sheet is needed.
Intricacies of amino acid sensing
The way in which cells sense amino acids derived from external proteins taken up by micropinocytosis and then degraded in the lysosome turns out to be different from ...the way in which they sense external amino acids taken up through transporters in the plasma membrane. Both sources of amino acids end up activating the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase complex. However, Hesketh
et al.
found that cultured human cells sense amino acids derived from exogenous proteins in late endosomes by a mechanism independent of the Rag guanosine triphosphatases (GTPases) that control mTORC1 activation in response to external amino acids. Furthermore, the GATOR GTPase had an inhibitory effect on mTORC1 activation in response to proteins processed through the lysosome, opposite to its role in sensing amino acids taken up across the plasma membrane.
Science
, this issue p.
351
How cells recognize amino acids derived from proteins processed in lysosomes is elucidated.
The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR–Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase–independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.
mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules ...(SGs) and processing bodies (PBs). Here, systematic in vivo proximity-dependent biotinylation (BioID) analysis of 119 human proteins associated with different aspects of mRNA biology uncovers 7424 unique proximity interactions with 1,792 proteins. Classical bait-prey analysis reveals connections of hundreds of proteins to distinct mRNA-associated processes or complexes, including the splicing and transcriptional elongation machineries (protein phosphatase 4) and the CCR4-NOT deadenylase complex (CEP85, RNF219, and KIAA0355). Analysis of correlated patterns between endogenous preys uncovers the spatial organization of RNA regulatory structures and enables the definition of 144 core components of SGs and PBs. We report preexisting contacts between most core SG proteins under normal growth conditions and demonstrate that several core SG proteins (UBAP2L, CSDE1, and PRRC2C) are critical for the formation of microscopically visible SGs.
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•We performed BioID on 119 human proteins involved in various facets of mRNA biology•Proximal relationships reveal the spatial organization of RNA regulatory structures•Prey-based analysis identifies 144 protein components of cytosolic RNA granules•UBAP2L, CSDE1, and PRRC2C are required for efficient formation of stress granules
Youn et al. performed proximity-based proteomics on 119 human proteins involved in the mRNA life cycle, focusing on cytosolic RNA granule components that are important for mRNA regulation. Systematic analysis of the proximal interactome revealed 144 core components of cytosolic RNA granules and illuminated the spatial organization of RNA regulatory structures.
The El Niño–Southern Oscillation (ENSO) has previously been shown to influence the winter North Atlantic Oscillation (NAO). Here we investigate the ENSO‐NAO teleconnection in historical and RCP8.5 ...scenario CMIP5 simulations and show a future strengthening of the teleconnection under RCP8.5. The teleconnection strength is associated with increased East Pacific tropical rainfall variability. Stratospheric and tropospheric teleconnection pathways are examined, with both pathways having stronger links in the future. The stratospheric pathway involves the Aleutian Low and the stratospheric polar vortex with a downward influence on the NAO. This pathway is clearest in the high‐top models that better resolve the stratosphere. The tropospheric pathway is driven by the Pacific subtropical jet strengthening and extending further into the Atlantic in the future, generating increased baroclinicity in the Caribbean and influencing the Atlantic storm track. These results suggest increasing influence of tropical rainfall on extratropical circulation in the future.
Plain Language Summary
Winter weather over Europe is driven by the North Atlantic Oscillation (NAO) an atmospheric circulation pattern linked to the fluctuating strength of westerly winds across the North Atlantic. Previous work has shown that the NAO is influenced by rainfall in the tropical East Pacific linked to the El Niño–Southern Oscillation (ENSO) an irregular warming and cooling of the tropical Pacific Ocean. We show that the ENSO‐NAO link strengthens in a future warmer climate according to climate models. Models with stronger links simulate bigger year‐to‐year changes in tropical east Pacific rainfall. We investigate two pathways in which the tropical rainfall influences the NAO. In the first pathway, the rainfall is linked to a persistent low‐pressure system over the North Pacific; this then weakens the winter stratospheric polar vortex, which in turn affects the NAO. The models that best simulate the stratosphere show this pathway is stronger in the future. In the second pathway, the jet stream over the Pacific extends further into the Atlantic in the future. This affects the Atlantic storm track, which is itself closely linked to the NAO. These results suggest that tropical rainfall has an increasing influence on the winter weather over Europe in the future, which may lead to better future predictability.
Key Points
CMIP5 models show a stronger link between NAO and ENSO in the future under climate change
Models with highest interannual tropical East Pacific rainfall variability show strongest effect
Results show potential for increased seasonal predictability of the NAO in the future
Compartmentalization is a defining characteristic of eukaryotic cells, and partitions distinct biochemical processes into discrete subcellular locations. Microscopy
and biochemical fractionation ...coupled with mass spectrometry
have defined the proteomes of a variety of different organelles, but many intracellular compartments have remained refractory to such approaches. Proximity-dependent biotinylation techniques such as BioID provide an alternative approach to define the composition of cellular compartments in living cells
. Here we present a BioID-based map of a human cell on the basis of 192 subcellular markers, and define the intracellular locations of 4,145 unique proteins in HEK293 cells. Our localization predictions exceed the specificity of previous approaches, and enabled the discovery of proteins at the interface between the mitochondrial outer membrane and the endoplasmic reticulum that are crucial for mitochondrial homeostasis. On the basis of this dataset, we created humancellmap.org as a community resource that provides online tools for localization analysis of user BioID data, and demonstrate how this resource can be used to understand BioID results better.
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