Microbiology
HIV fusion: Catch me if you can
The penetration of enveloped viruses into target cells requires the fusion of the lipid envelope of their virions with the host lipid membrane though a stepwise and highly sophisticated process. However, the intermediate steps in this process have seldom been visualized due to their rarity and rapidity. Here, using cryo-electron tomography, TIRF microscopy, and cell membrane–derived vesicles called blebs, Ward et al. visualize intermediates of the HIV-cell membrane fusion process and demonstrate how Serinc proteins prevent full fusion by interfering with this process.Taking the “Me” out of meat: A new demethylation pathway dismantles a toxin's precursor
Carnitine, a molecule found in red meat, is metabolized to trimethylamine (TMA) by the gut microbiota. TMA is then converted in the liver to trimethylamine oxide, a causative agent for atherosclerosis. Kountz et al. have discovered an alternative pathway for carnitine metabolism in the gut bacterium Eubacterium limosum. Instead of forming TMA, carnitine is demethylated by the newly discovered methyltransferase MtcB, sending one-carbon units into production of short-chain fatty acids. These results suggest that bacterial metabolic activities could promote cardiovascular health by preventing the buildup of toxin precursors.Finding proteases that make cells go viral
The activation of influenza virus hemagglutinin (HA) glycoprotein via cleavage by host cell proteases is essential for viral infectivity, and understanding the mechanisms for HA protein cleavage and how they may differ depending on the biological context is important for the development of flu treatments. However, the HA proteases involved in the activation of many viral strains remain unidentified. In this issue, Harbig et al. identify a repertoire of proteases that cleave HA and determine the proteases' functionality against specific HA glycoproteins.Unequal twins: Unraveling the reaction mechanism of dimeric histidine kinases
Histidine kinases (HKs), together with their partner proteins, the response regulators (RRs), form the ubiquitous two-component systems that are global players in control and adjustment of microbial lifestyle. Although their basic function (i.e. the transfer of a phosphate group from the HK to its RR partner) is simple to articulate, deciphering the molecular details of this process has proven anything but simple, especially when quantitative aspects come into play. Bouillet et al. report a series of elegant and sophisticated experiments to quantitatively understand HK functions, clearing up several open questions and providing a new strategy for future work in the field.Halting coronavirus polymerase
The nucleotide analogue remdesivir is an investigational drug for the treatment of human coronavirus infection. Remdesivir is a phosphoramidate prodrug and is known to target viral RNA-dependent RNA polymerases. In this issue, Gordon et al. identify that remdesivir acts as a delayed RNA chain terminator for MERS-CoV polymerase complexes.Self-control of vitamin K2 production captured in the crystal
Menaquinone (MK) or vitamin K2 is an important metabolite that controls the redox/energy status of Mycobacterium tuberculosis. Although the major steps of MK biosynthesis have been delineated, the regulatory mechanisms of this pathway have not been adequately explored. Bashiri et al. now demonstrate that MenD, catalyzing the first committed step of MK production, is allosterically inhibited by a downstream cytosolic metabolite in the MK biosynthesis pathway.Catching protein polyphosphorylation in the act
Lysine polyphosphorylation (K-PPn) is a relatively new post-translational modification, the full targets and functional consequences of which are unknown. A critical problem in the study of endogenous K-PPn of proteins in the yeast model system is that its nonenzymatic nature and its susceptibility to polyphosphatases make it potentially susceptible to artifacts during extraction. A new study confirms that K-PPn modifications can be altered during sample handling, provides new insights into the mechanism of K-PPn, and develops a yeast model strain, devoid of both vacuolar polyP and polyphosphatases, that allows detection of authentic endogenous K-PPn.Cryo-EM cools down swine fever
African swine fever virus (ASFV) is among the most complex DNA viruses known. Outbreaks have killed millions of swine around the world, and there is currently no vaccine. Three recent papers report the cryo-EM structure of the complete ASFV virion, comprising a viral particle of multiple layers, and resolve the major outer-capsid protein p72 to higher resolution. Progress in these reports provides a further understanding of the structure-function relationships of large viruses and should aid in ASFV vaccine development.The work of Konrad Bloch's laboratory on unsaturated fatty acid biosynthesis in bacteria
Lipids are ubiquitous molecules, serving as the structural building blocks for membranes, messengers in cell signaling, or compounds for energy storage. Their functional versatility relies in part on the presence of one or more double bonds in the long lipid carbon chains. The more double bonds there are in a lipid, the more unsaturated it is; and the more unsaturated lipids there are in a membrane, the more flexible the membrane tends to be. Cells take advantage of this property by fine-tuning the levels of saturated and unsaturated fatty acids in membranes to external conditions and required membrane function.Inorganic polyphosphate accumulation suppresses the dormancy response and virulence in Mycobacterium tuberculosis
Stringent response pathways involving inorganic polyphosphate (PolyP) play an essential role in bacterial stress adaptation and virulence. The intracellular levels of PolyP are modulated by the activities of polyphosphate kinase-1 (PPK1), polyphosphate kinase-2 (PPK2), and exopolyphosphatases (PPXs). The genome of Mycobacterium tuberculosis encodes two functional PPXs, and simultaneous deletion of ppx1 and ppx2 results in a defect in biofilm formation. We demonstrate here that these PPXs cumulatively contribute to the ability of M.Weaponizing T-cell receptors through molecular engineering
T-cell receptors (TCRs) recognize pathogens to ignite immune responses, making them attractive scaffolds for development as immunotherapeutics. However, manipulation of TCRs has been impeded by difficulties in their engineering and expression. Wagner and colleagues now establish new platforms to generate high-affinity TCR variants that potently activate T cells, and they also create soluble TCR fusion proteins that specifically recognize cognate peptides. This work provides specific tools to combat cytomegalovirus (CMV) infection and helps illuminate a general path to actuation of engineered TCR-based therapeutics.Let's get this pyrin started!
Inflammasomes enable cells to respond to pathogens or biological damage, but the specific signals being used to convey these messages are not always clear. A new paper identifies two potential microbiota-derived metabolites, the bile acid analogues BAA485 and BAA473, as the first small molecules to activate the pyrin inflammasome. These results suggest that microbiota may be able to modulate this inflammatory process which, in turn, may contribute to the maintenance of intestinal homeostasis.Mycobacterium tuberculosis EsxL inhibits MHC-II expression by promoting hypermethylation in class-II transactivator loci in macrophages
Mycobacterium tuberculosis is known to modulate the host immune responses to facilitate its persistence inside the host cells. One of the key mechanisms includes repression of class-II transactivator (CIITA) and MHC-II expression in infected macrophages. However, the precise mechanism of CIITA and MHC-II down-regulation is not well studied. M. tuberculosis 6-kDa early secretory antigenic target (ESAT-6) is a known potent virulence and antigenic determinant. The M. tuberculosis genome encodes 23 such ESAT-6 family proteins.The Streptococcus gordonii Adhesin CshA Protein Binds Host Fibronectin via a Catch-Clamp Mechanism
Adherence of bacteria to biotic or abiotic surfaces is a prerequisite for host colonization and represents an important step in microbial pathogenicity. This attachment is facilitated by bacterial adhesins at the cell surface. Because of their size and often elaborate multidomain architectures, these polypeptides represent challenging targets for detailed structural and functional characterization. The multifunctional fibrillar adhesin CshA, which mediates binding to both host molecules and other microorganisms, is an important determinant of colonization by Streptococcus gordonii, an oral commensal and opportunistic pathogen of animals and humans.The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism
Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion.Yeast Tolerance to Various Stresses Relies on the Trehalose-6P Synthase (Tps1) Protein, Not on Trehalose
Background: Decades of observations strengthened the idea that trehalose is a chemical chaperone.Results: A catalytically inactive variant of the trehalose-6P synthase (Tps1) maintains cell survival and energy homeostasis under stress exposure.Conclusion: The Tps1 protein itself, not trehalose, is crucial for cell integrity.Significance: This work provides unbiased evidence for an alternative function of Tps1, a new “moonlighting” protein.
