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The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis 期刊论文
NATURE, 2020, 580 (7804) : 530-+
作者:  Erler, Janine T.;  Bennewith, Kevin L.;  Nicolau, Monica;  Dornhofer, Nadja;  Kong, Christina;  Le, Quynh-Thu;  Chi, Jen-Tsan Ashley;  Jeffrey, Stefanie S.;  Giaccia, Amato J.
收藏  |  浏览/下载:48/0  |  提交时间:2020/07/03

Phosphorylation of INSIG1 and INSIG2 by PCK1 leads to a reduction in the binding of sterols, the activation of SREBP1 and SREBP2 and the downstream transcription of lipogenesis-associated genes that promote tumour growth.


Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs(1,2). However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.


  
The ABC exporter IrtAB imports and reduces mycobacterial siderophores 期刊论文
NATURE, 2020, 580 (7803) : 413-+
作者:  Fessler, Evelyn;  Eckl, Eva-Maria;  Schmitt, Sabine;  Mancilla, Igor Alves;  Meyer-Bender, Matthias F.;  Hanf, Monika;  Philippou-Massier, Julia;  Krebs, Stefan;  Zischka, Hans;  Jae, Lucas T.
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

Intracellular replication of the deadly pathogen Mycobacterium tuberculosis relies on the production of small organic molecules called siderophores that scavenge iron from host proteins(1). M. tuberculosis produces two classes of siderophore, lipid-bound mycobactin and water-soluble carboxymycobactin(2,3). Functional studies have revealed that iron-loaded carboxymycobactin is imported into the cytoplasm by the ATP binding cassette (ABC) transporter IrtAB(4), which features an additional cytoplasmic siderophore interaction domain(5). However, the predicted ABC exporter fold of IrtAB is seemingly contradictory to its import function. Here we show that membrane-reconstituted IrtAB is sufficient to import mycobactins, which are then reduced by the siderophore interaction domain to facilitate iron release. Structure determination by X-ray crystallography and cryo-electron microscopy not only confirms that IrtAB has an ABC exporter fold, but also reveals structural peculiarities at the transmembrane region of IrtAB that result in a partially collapsed inward-facing substrate-binding cavity. The siderophore interaction domain is positioned in close proximity to the inner membrane leaflet, enabling the reduction of membrane-inserted mycobactin. Enzymatic ATPase activity and in vivo growth assays show that IrtAB has a preference for mycobactin over carboxymycobactin as its substrate. Our study provides insights into an unusual ABC exporter that evolved as highly specialized siderophore-import machinery in mycobacteria.


  
Global-scale human impact on delta morphology has led to net land area gain 期刊论文
NATURE, 2020, 577 (7791) : 514-+
作者:  Nienhuis, J. H.;  Ashton, A. D.;  Edmonds, D. A.;  Hoitink, A. J. F.;  Kettner, A. J.;  Rowland, J. C.;  Tornqvist, T. E.
收藏  |  浏览/下载:43/0  |  提交时间:2020/05/13

River deltas rank among the most economically and ecologically valuable environments on Earth. Even in the absence of sea-level rise, deltas are increasingly vulnerable to coastal hazards as declining sediment supply and climate change alter their sediment budget, affecting delta morphology and possibly leading to erosion(1-3). However, the relationship between deltaic sediment budgets, oceanographic forces of waves and tides, and delta morphology has remained poorly quantified. Here we show how the morphology of about 11,000 coastal deltas worldwide, ranging from small bayhead deltas to mega-deltas, has been affected by river damming and deforestation. We introduce a model that shows that present-day delta morphology varies across a continuum between wave (about 80 per cent), tide (around 10 per cent) and river (about 10 per cent) dominance, but that most large deltas are tide- and river-dominated. Over the past 30 years, despite sea-level rise, deltas globally have experienced a net land gain of 54 +/- 12 square kilometres per year (2 standard deviations), with the largest 1 per cent of deltas being responsible for 30 per cent of all net land area gains. Humans are a considerable driver of these net land gains-25 per cent of delta growth can be attributed to deforestation-induced increases in fluvial sediment supply. Yet for nearly 1,000 deltas, river damming(4) has resulted in a severe (more than 50 per cent) reduction in anthropogenic sediment flux, forcing a collective loss of 12 +/- 3.5 square kilometres per year (2 standard deviations) of deltaic land. Not all deltas lose land in response to river damming: deltas transitioning towards tide dominance are currently gaining land, probably through channel infilling. With expected accelerated sea-level rise(5), however, recent land gains are unlikely to be sustained throughout the twenty-first century. Understanding the redistribution of sediments by waves and tides will be critical for successfully predicting human-driven change to deltas, both locally and globally.


A global study of river deltas shows a net increase in delta area by about 54 km(2) yr(-1) over the past 30 years, in part due to deforestation-induced sediment delivery increase.


  
Wood quality of black spruce and balsam fir trees defoliated by spruce budworm: A case study in the boreal forest of Quebec, Canada 期刊论文
FOREST ECOLOGY AND MANAGEMENT, 2019, 437: 201-210
作者:  Paixao, Carlos;  Krause, Cornelia;  Morin, Hubert;  Achim, Alexis
收藏  |  浏览/下载:18/0  |  提交时间:2019/04/09
Spruce budworm outbreak  Wood quality  Picea mariana  Abies balsamea  Growth reduction  Wood density  Lumen area  Cell-wall thickness  Earlywood  Latewood