Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B’/B and C’/C. POST1 promotes the generation of the functional S1P-C’/C from S1P-B’/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β-subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.
The construction of a high-speed railway is important to the transportation network and economic development of a region. To further understand the interaction between accessibility and urban economic linkage in the context of high-speed railway networks, this study investigated the spatial and temporal changes in the coupling coordination between accessibility and economic linkage after a high-speed railway was opened in Hunan Province, China, using a coupling coordination model. The aim of this research is to explore the role that high-speed rail construction plays in regional development. Results indicate that (1) after the high-speed railway was opened, the accessibility of cities in Hunan Province has improved significantly, although the overall pattern has not changed by much. This is because it still shows a radiation pattern, with the Changsha–Zhuzhou–Xiangtan urban agglomeration at its core, which has subsequently spread to surrounding areas; (2) the improvement in urban accessibility has strengthened the economic linkages between cities, and the overall spatial pattern has gradually evolved from a point-axis pattern to a network pattern. The bipolar trend of total regional economic linkage has become more pronounced than what it was before; (3) the overall coordination degree of accessibility and economic linkage coupling in Hunan Province is primary coupling, and the phenomenon of regional polarization is prominent, thus showing the overall spatial pattern of ‘strong in the east and weak in the west.’ Further strengthening the construction of the high-speed railway in the northern part of Hunan, promoting the economic construction in the western and southern parts of Hunan, and building a spatial pattern of synergistic integration for Hunan’s continued transportation and economic development are suggested.
In the context of accelerated urbanization, constructing resilient cities is an effective approach to tackling risks, such as extreme weather, and various urban challenges. The coupling and coordinated development of urbanization and urban resilience is a prominent embodiment of urban sustainable development and high-quality development capacity. In this study, Hunan Province, China, which is frequently affected by various disasters, is selected as a representative for examining the coupling and coordination relationship between urban resilience and urbanization level. The panel data are adopted to construct a dual-system evaluation framework integrating urban resilience and urbanization level based on the entropy weight-coefficient of variation (CV)-CRITIC method. The coupling coordination degree of this dual-system evaluation framework is calculated with the coupling model in physics and GM (1, 1) grey prediction model. Additionally, the spatial–temporal evolution characteristics of the coupling coordination degree are investigated and analyzed by ArcGIS and Geoda software. The following are indicated from the results: (1) The resilience of all cities is related to their geographical location and is characterized by a decrease from east to west; in addition, the resilience level of most cities presents a downward trend with time. (2) The urbanization level of most cities develops stably with time, but there is a growing gap in the urbanization level between regions. (3) There is a strong correlation between urban resilience and urbanization level in all cities; the unbalanced coupling and coordinated development emerge, specifically manifested by the polarization phenomenon. Eventually, a circle-difference spatial distribution pattern that starts from the central urban agglomeration and gradually decreases to the periphery is formed. (4) The prediction results of the coupling coordination degree suggest that there is an increasingly distinct polarization trend for the coupling and coordinated development between cities, and it is necessary to pay attention to those cities with a declined predicted value. (5) There is a significant positive spatial autocorrelation and agglomeration effects in the distribution of the coupling coordination degree of all cities, and the correlation is getting stronger with each passing year; the correlation mode is mainly characterized by homogeneity and supplemented by heterogeneity. Finally, several suggestions are proposed in this paper, in an attempt to lead the coordinated development of regions by novel urbanization and thus promote the sustainable development of cities. The methods and insights adopted in this study contribute to investigating the relationship between urban resilience and urbanization in China and other regions worldwide.
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