During its first two and a half months, the recently emerged 2019 novel coronavirus, SARS-CoV-2, has already infected over one-hundred thousand people worldwide and has taken more than four thousand lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge, we leveraged data about the related coronaviruses that is readily available in public databases and integrated these data into a single computational pipeline. As a result, we provide comprehensive structural genomics and interactomics roadmaps of SARS-CoV-2 and use this information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community.Having infected over a hundred thousand people in more than a hundred countries across the globe, the new coronavirus, SARS-CoV-2, has a major health and economic impact worldwide. With a genome of the new virus sequenced, scientists learned that this virus is closely related to other coronaviruses, such as SARS-CoV and MERS-CoV. This discovery, however, leads to other questions. How different are the proteins of SARS-CoV-2, its main functional building blocks, from those of SARS-CoV? Does the new virus target the same proteins in human cells as the known coronaviruses? Most importantly, can the currently developed SARS or MERS antiviral drug candidates or other promising compounds be used to treat the new infection? This study lays out the first 3D roadmap of SARS-CoV-2 viral proteins and their functional complexes, enabling scientists to answer the above questions. The roadmap can be used to streamline the search for new antivirals and vaccines.

Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.

The mammalian STE20-like protein kinase 1 (MST1)-MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST-MOB complexes are also involved in regulating Hippo-YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4-MOB4 complex resembles that of the MST1-MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1-MOB1 complex, the MST4-MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1-MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4-MOB4 complex as a noncanonical regulator of the Hippo-YAP pathway with an oncogenic role in PC. Our findings highlight that although MST-MOB complexes display some structural conservation, they functionally diverged during their evolution.

Phlorizin exists in a number of fruits and foods and exhibits many bioactivities. The mechanism of its antidiabetic effect has been known as it can competitively inhibit sodium-glucose symporters (SGLTs). However, phlorizin has a wide range of two-phase metabolism in systemic circulation and shows poor oral bioavailability. An alternative mechanism may involve gut microbiota in intestine. Sixteen obese mice with type 2 diabetes (db/db) and eight age-matched control mice (db/+) were divided into three groups: diabetic group treated with phlorizin (DMT group), vehicle-treated diabetic group (DM group), and normal control group (CC group). Phlorizin was given in normal saline solution by intragastric administration for 10 weeks. After the last treatment course, body weight, energy intake, serum lipopolysaccharides (LPS), insulin resistance, and fecal short-chain fatty acids (SCFAs) were compared. 16S rRNA gene denaturing gradient gel electrophoresis (DGGE) and quantitative PCR were used to determine the changes in microbiome composition. Coadministration of phlorizin significantly prevented metabolic syndrome by decreasing weight gain, energy intake, serum lipopolysaccharides, and insulin resistance, and the fecal level of total SCFAs was dramatically increased, especially butyric acid. DGGE and quantitative PCR demonstrated that phlorizin coadministration increased the gut microbial diversity and the growth of Akkermansia muciniphila and Prevotella. Meanwhile, the gut microbiota structure of db/db mice after phlorizin treatment was improved and approached the normal group. The mechanism of the hypoglycemic action of phlorizin is associated with LPS decrease and gut microbiota changes; briefly, it acts in the intestine to modify gut microbial community structure, resulting in lower LPS load in the host and higher SCFAs producing beneficial bacteria.