C. elegans screen identifies autophagy genes specific to multicellular organisms.

The molecular understanding of autophagy has originated almost exclusively from yeast genetic studies. Little is known about essential autophagy components specific to higher eukaryotes. Here we perform genetic screens in C. elegans and identify four metazoan-specific autophagy genes, named epg-2, -3, -4, and -5. Genetic analysis reveals that epg-2, -3, -4, and -5 define discrete genetic steps of the autophagy pathway. epg-2 encodes a coiled-coil protein that functions in specific autophagic cargo recognition. Mammalian homologs of EPG-3/VMP1, EPG-4/EI24, and EPG-5/mEPG5 are essential for starvation-induced autophagy. VMP1 regulates autophagosome formation by controlling the duration of omegasomes. EI24 and mEPG5 are required for formation of degradative autolysosomes. This study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway and provides mechanistic insights into the metazoan-specific autophagic process.

An industrial structure adjustment model to facilitate high-quality development of an eco-industrial park.

The tradeoff between economic growth and environmental protection has been a critical issue in facilitating eco-industrial park development in China. As the principal contributors to China's industrial output, many industrial parks have been addressing the issues of intensive resource consumption and pollutant generation, driven by much stricter regulations on the environment and resource management. Retuning the industrial structure is a substantial way to address the environmental issues while promoting economic development, which are the goals of eco-industrial development. This study proposes a multi-criteria industrial structure adjustment model by employing a generalized reduced gradient method to find the optimal structure of an industrial park. The model aims to increase the overall resource utilization efficiency and industrial output efficiency through a decoupling between the economic development and environmental burden of the park. A Chinese eco-industrial park located in the capital, the Beijing Economic-technological Development Area (BDA), is used as an example to uncover a transformation roadmap from a high-speed mode to a high-quality mode. The constraints of the multi-criteria decision-making model mainly focus on the limits of water consumption and pollutant emissions by targeting an appropriate economic development rate. The key findings are as follows. First, BDA could achieve 186% economic growth with 20% water consumption and 30% contaminant reduction in five years (2020-2025) by optimizing the industrial structure. Second, the advanced manufacturing industries play significant roles in stimulating the high-quality development. Third, ammonia nitrogen is a crucial factor restricting economic development under the requests of the "dual control" policy. Forth, the industry that can use reclaimed water in production will get more development opportunities and space, and vice versa. The model can be applied in diverse industrial parks by modifying the parameters and associated constraints.

Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein.

The Beclin 1 gene is a haplo-insufficient tumor suppressor and plays an essential role in autophagy. However, the molecular mechanism by which Beclin 1 functions remains largely unknown. Here we report the crystal structure of the evolutionarily conserved domain (ECD) of Beclin 1 at 1.6 Å resolution. Beclin 1 ECD exhibits a previously unreported fold, with three structural repeats arranged symmetrically around a central axis. Beclin 1 ECD defines a novel class of membrane-binding domain, with a strong preference for lipid membrane enriched with cardiolipin. The tip of a surface loop in Beclin 1 ECD, comprising three aromatic amino acids, acts as a hydrophobic finger to associate with lipid membrane, consequently resulting in the deformation of membrane and liposomes. Mutation of these aromatic residues rendered Beclin 1 unable to stably associate with lipid membrane in vitro and unable to fully rescue autophagy in Beclin 1-knockdown cells in vivo. These observations form an important framework for deciphering the biological functions of Beclin 1.

The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes.

PtdIns(3)P plays critical roles in the autophagy pathway. However, little is known about how PtdIns(3)P effectors act with autophagy proteins in autophagosome formation. Here we identified an essential autophagy gene in C. elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity. EPG-6 directly interacts with ATG-2. epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures. Another WD40 repeat PtdIns(3)P effector, ATG-18, plays a distinct role in autophagosome formation. We also established the hierarchical relationship of autophagy genes in degradation of protein aggregates and revealed that the UNC-51/Atg1 complex, EPG-8/Atg14, and binding of lipidated LGG-1 to protein aggregates are required for omegasome formation. Our study demonstrates that autophagic PtdIns(3)P effectors play distinct roles in autophagosome formation and also provides a framework for understanding the concerted action of autophagy genes in protein aggregate degradation.