Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.

Acinetobacter baumannii is undoubtedly one of the most successful pathogens responsible for hospital-acquired nosocomial infections in the modern healthcare system. Due to the prevalence of infections and outbreaks caused by multi-drug resistant A. baumannii, few antibiotics are effective for treating infections caused by this pathogen. To overcome this problem, knowledge of the pathogenesis and antibiotic resistance mechanisms of A. baumannii is important. In this review, we summarize current studies on the virulence factors that contribute to A. baumannii pathogenesis, including porins, capsular polysaccharides, lipopolysaccharides, phospholipases, outer membrane vesicles, metal acquisition systems, and protein secretion systems. Mechanisms of antibiotic resistance of this organism, including acquirement of β-lactamases, up-regulation of multidrug efflux pumps, modification of aminoglycosides, permeability defects, and alteration of target sites, are also discussed. Lastly, novel prospective treatment options for infections caused by multi-drug resistant A. baumannii are summarized.

Klebsiella pneumoniae is one of the most clinically relevant species in immunocompromised individuals responsible for community-acquired and nosocomial infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Since the mid-1980s, hypervirulent K. pneumoniae, generally associated with the hypermucoviscosity phenotype, has emerged as a clinically significant pathogen responsible for serious disseminated infections, such as pyogenic liver abscesses, osteomyelitis, and endophthalmitis, in a generally younger and healthier population. Hypervirulent K. pneumoniae infections were primarily found in East Asia and now are increasingly being reported worldwide. Although most hypervirulent K. pneumoniae isolates are antibiotic-susceptible, some isolates with combined virulence and resistance, such as the carbapenem-resistant hypervirulent K. pneumoniae isolates, are increasingly being detected. The combination of multidrug resistance and enhanced virulence has the potential to cause the next clinical crisis. To better understand the basic biology of hypervirulent K. pneumoniae, this review will provide a summarization and discussion focused on epidemiology, hypervirulence-associated factors, and antibiotic resistance mechanisms of such hypervirulent strains. Epidemiological analysis of recent clinical isolates in China warns the global dissemination of hypervirulent K. pneumoniae strains with extensive antibiotic resistance in the near future. Therefore, an immediate response to recognize the global dissemination of this hypervirulent strain with resistance determinants is an urgent priority.

SummaryThe differentiating bacterium Streptomyces coelicolor harbours some 66 sigma factors, which support its complex life cycle.

The protein kinase mammalian target of rapamycin (mTOR) plays an important role in the coordinate regulation of cellular responses to nutritional and growth factor conditions. mTOR achieves these roles through interacting with raptor and rictor to form two distinct protein complexes, mTORC1 and mTORC2. Previous studies have been focused on mTORC1 to elucidate the central roles of the complex in mediating nutritional and growth factor signals to the protein synthesis machinery. Cell growth relies on coordinated regulation of signaling pathways that integrate cellular physiological status in response to nutrient levels, growth factor signals, and environmental stress. Impairment of the coordinated regulation can lead to disastrous effects on cell physiology, resulting in cell death or uncontrolled growth. mTOR, 2 a member of the phosphatidylinositol kinase-related kinase family, has been known as a central player in the signaling pathway that regulates cell growth in response to a variety of cellular signals derived from nutrient levels, growth factors, and environmental stress (2-4). mTOR plays a central role in the signaling network that regulates a variety of cellular processes including ribosome biogenesis, protein synthesis, autophagy, and actin cytoskeleton organization; human diseases such as cancer, diabetes, obesity, and harmatoma syndrome are associated with defects in mTOR signaling (5-9).Recent years have seen discoveries of several mTOR effectors and binding proteins. mTOR exists in two multiprotein complexes, mTORC1 and mTORC2. mTORC1 consists of mTOR, raptor, G␤L, and PRAS40, and it functions to regulate protein synthesis and cell growth in response to nutrient levels and growth factor signals (10 -14). mTORC1 regulates phosphorylations of at least two regulators of protein synthesis, S6K1 and 4E-BP1, and mediates nutrient and insulin signals to the cell growth machinery (2, 15). mTORC1 is regulated by TSC-Rheb (tuberous sclerosis complex-Ras homolog-enriched in brain) signaling (16 -19). mTORC2 consists of mTOR, rictor, G␤L, and Sin1, and it does not likely bind rapamycin-FK506-binding protein 12 complex, which makes mTORC2 distinctive from mTORC1 (13,20,21). Saccharomyces cerevisiae TORC2 consists of TOR2, LST8, AVO1 (Sin1 ortholog), and AVO3 (rictor ortholog) and two other components, AVO2 and BIT61, whose homologues have not been identified in higher eukaryotes (13,22,23). Functions and regulatory mechanisms of mTORC2 remain largely unknown. Recent studies showed that mTORC2 regulates protein kinase C ␣ phosphorylation, actin cytoskeleton organization, and Akt phosphorylation at 21,24,25). Recognizing the complex relationship between mTOR, S6K1, and * This study was supported by the Tuberous Sclerosis Alliance, the Minnesota Medical Foundation, American Heart Association Grant 0655706Z, and National Institutes of Health Grant DK072004. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in acc...