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ABSTRACTThe phase separated SQSTM1/p62 body drives the formation of autophagosomes during macroautophagy/autophagy. However, the underlying mechanism by which the SQSTM1/p62 body acts during this process remains less understood. Recently, we reported that the SQSTM1/p62 body can work as a nucleation center to recruit local membrane sources for the expanding phagophore. Proteomics analysis reveals membrane vesicle-related components as important constituents of the SQSTM1/p62 body. ATG9- and ATG16L1-positive vesicles are recruited by the SQSTM1/p62 body as initial membrane sources of phagophores. ATG2 promotes the lipid transfer and vesicle fusion to further expand the membrane architecture of the initial phagophore. The lipid composition and content within the SQSTM1/p62 body is significantly affected by ATG2. The SQSTM1/p62 body also regulates the proper positioning and abundance of ATG9-positive vesicles. Furthermore, by spatially gathering ULK1 and membrane-anchored class III phosphatidylinositol (PtdIns) 3-kinase complexes, the SQSTM1/p62 body acts a local reaction platform to generate PtdIns-3-phosphate (PtdIns3P) to accelerate autophagosome maturation. These findings highlight a lipid membrane gathering model of the multifaceted SQSTM1/p62 body when driving autophagosome formation.

Biomolecular condensation driven by liquid–liquid phase separation (LLPS) is key to assembly of membraneless organelles in numerous crucial pathways. It is largely unknown how cellular structures or components spatiotemporally regulate LLPS and condensate formation. Here we reveal that cytoskeletal dynamics can control the condensation of p62 bodies comprising the autophagic adaptor p62/SQSTM1 and poly-ubiquitinated cargos. Branched actin networks are associated with p62 bodies and are required for their condensation. Myosin 1D, a branched actin-associated motor protein, drives coalescence of small nanoscale p62 bodies into large micron-scale condensates along the branched actin network. Impairment of actin cytoskeletal networks compromises the condensation of p62 bodies and retards substrate degradation by autophagy in both cellular models and Myosin 1D knockout mice. Coupling of LLPS scaffold to cytoskeleton systems may represent a general mechanism by which cells exert spatiotemporal control over phase condensation processes.

Recent researches have reported that long noncoding RNA (lncRNA) five prime to Xist (FTX) plays a crucial role in the initiation and progression of cancers. In the current study, the clinical significance and functional roles of lncRNA FTX in colorectal cancer (CRC) progression were investigated. A significant increase of lncRNA FTX expression in CRC tissue and cell lines was observed. Overexpression of lncRNA FTX was significantly associated with the bigger tumor diameter, the advanced TNM stage, the lymph node, and distant metastasis, and also predicted poor prognosis of patients with CRC. Functional analyses demonstrated that knockdown of lncRNA FTX markedly inhibited CRC cell proliferation, migration, and invasion in vitro. Mechanistically, FTX directly interacted with miR-215 and suppressed miR-215 expression. FTX also bind to vimentin and reduced its phosphorylation level on Ser83 in CRC cells. Finally, using siRNAs against lncRNA FTX could dramatically inhibit CRC growth and distant metastasis in vivo. Taken together, our data demonstrated an oncogenic role of lncRNA FTX in CRC tumorigenesis and progression via interaction with miR-215 and vimentin. Then, a promising therapeutic target for CRC was provided.

Atom-Centered Multilayer Code (ACMC) is a novel coding algorithm by characterizing the sphere environment of a non-hydrogen atom, called center atom. This algorithm starts from the center atom and then develops to its environment layer by layer automatically without predefining specific fragments, and the number of layers is determined on the structure of the coded compound without limit. Fast searching strategy at the atomic level is obtained by using this code. The coding process and the global structure and substructure searching are discussed with examples.