Residue Y362 is crucial for FLIP to impart catalytic activity to pro-caspase-8 to suppress necroptosis.

The pro-form of caspase-8 prevents necroptosis by functioning in a proteolytically active complex with its catalytic-dead homolog, FLICE (FADD [Fas-associated death domain]-like interleukin 1β-converting enzyme)-like inhibitory protein long-form (FLIP). However, how FLIP imparts caspase-8 the catalytic activity to suppress necroptosis remains elusive. Here, we show that the protease-like domain of FLIP is essential for the activity of the caspase-8-FLIP heterodimer in blocking necroptosis.

Hydrogen peroxide-induced oxidative damage and protective role of peroxiredoxin 6 protein via EGFR/ERK signaling pathway in RPE cells.

Introduction: Damage to retinal pigment epithelium (RPE) cells caused by oxidative stress is closely related to the pathogenesis of several blinding retinal diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and other inherited retinal degenerative conditions. However, the mechanisms of this process are poorly understood. Hence, the goal of this study was to investigate hydrogen peroxide (HO)-induced oxidative damage and protective role of peroxiredoxin 6 (PRDX6) protein via EGFR/ERK signaling pathway in RPE cells.

Atypical GTPase effector hijacks host vesicular transport factor p115 to regulate host lipid droplet.

The intracellular bacterial pathogen uses hundreds of effector proteins to manipulate multiple processes of the host cells to establish a replicative niche known as -containing vacuole (LCV). Biogenesis of the LCV has been known to depend on host small guanosine triphosphatases (GTPases), but whether bacterial effector GTPases are also involved remains unknown. Here, we show that an ankyrin repeat containing effector LegA15 localizes directly in host lipid droplets (LDs), leading to Golgi apparatus fragmentation of the host cells by hijacking the host vesicular transport factor p115.

The Staphylococcus aureus cell division protein, DivIC, interacts with the cell wall and controls its biosynthesis.

Bacterial cell division is a complex, dynamic process that requires multiple protein components to orchestrate its progression. Many division proteins are highly conserved across bacterial species alluding to a common, basic mechanism. Central to division is a transmembrane trimeric complex involving DivIB, DivIC and FtsL in Gram-positives.

Structural basis for the acetylation mechanism of the Legionella effector VipF.

The pathogen Legionella pneumophila, which is the causative agent of Legionnaires' disease, secrets hundreds of effectors into host cells via its Dot/Icm secretion system to subvert host-cell pathways during pathogenesis. VipF, a conserved core effector among Legionella species, is a putative acetyltransferase, but its structure and catalytic mechanism remain unknown. Here, three crystal structures of VipF in complex with its cofactor acetyl-CoA and/or a substrate are reported.

The W-Acidic Motif of Histidine Kinase WalK Is Required for Signaling and Transcriptional Regulation in .

In , we find that the histidine kinase WalK possesses the longest C-terminal tail (CTT) among all 14 TCSs, and this tail plays a key role in the interaction of WalK with its response regulator WalR. We demonstrate that the intrinsically disordered CTT is characterized by a conserved tryptophan residue surrounded by acidic amino acids. Mutation in the tryptophan not only disrupts the stable interaction, but also impairs the efficient phosphotransferase and phosphatase activities of WalRK.

Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.

GLS1 orchestrates glutaminolysis and promotes cell proliferation when glutamine is abundant by regenerating TCA cycle intermediates and supporting redox homeostasis. CB-839, an inhibitor of GLS1, is currently under clinical investigation for a variety of cancer types. Here, we show that GLS1 facilitates apoptosis when glutamine is deprived.

Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability.

Astrocyte aerobic glycolysis provides vital trophic support for central nervous system neurons. However, whether and how astrocytic metabolic dysregulation contributes to neuronal dysfunction in intellectual disability (ID) remain unclear. Here, we demonstrate a causal role for an ID-associated SNX27 mutation (R198W) in cognitive deficits involving reshaping astrocytic metabolism.

Demonstration of the role of cell wall homeostasis in growth and the action of bactericidal antibiotics.

Bacterial cell wall peptidoglycan is essential, maintaining both cellular integrity and morphology, in the face of internal turgor pressure. Peptidoglycan synthesis is important, as it is targeted by cell wall antibiotics, including methicillin and vancomycin. Here, we have used the major human pathogen to elucidate both the cell wall dynamic processes essential for growth (life) and the bactericidal effects of cell wall antibiotics (death) based on the principle of coordinated peptidoglycan synthesis and hydrolysis.

Biphasic regulation of transcriptional surge generated by the gene feedback loop in a two-component system.

Motivation: Transcriptional surges generated by two-component systems (TCSs) have been observed experimentally in various bacteria. Suppression of the transcriptional surge may reduce the activity, virulence and drug resistance of bacteria. In order to investigate the general mechanisms, we use a PhoP/PhoQ TCS as a model system to derive a comprehensive mathematical modeling that governs the surge.

The metaeffector MesI regulates the activity of the Legionella effector SidI through direct protein-protein interactions.

To create an intracellular niche permissive for its replication, Legionella pneumophila uses hundreds of effectors to target a wide variety of host proteins and manipulate specific host processes such as immune response, and vesicle trafficking. To avoid unwanted disruption of host physiology, this pathogen also imposes precise control of its virulence by the use of effectors called metaeffectors to regulate the activity of other effectors. A number of effector/metaeffector pairs with distinct regulatory mechanisms have been characterized, including abrogation of protein modifications, direct modification of the effector and direct binding to the catalytic pocket of the cognate effector.

Structural insights into the signal transduction mechanism of the K-sensing two-component system KdpDE.

Two-component systems (TCSs), which consist of a histidine kinase (HK) sensor and a response regulator (RR), are important for bacteria to quickly sense and respond to various environmental signals. HKs and RRs typically function as a cognate pair, interacting only with one another to transduce signaling. Precise signal transduction in a TCS depends on the specific interactions between the receiver domain (RD) of the RR and the dimerization and histidine phosphorylation domain (DHp) of the HK.

Interacting proteins of the essential two-component system YycFG in Bacillus subtilis.

Two-component signal transduction systems (TCSs) play a major role in adaption and survival of microorganisms in a dynamic and sometimes dangerous environment. YycFG is an essential TCS for many Gram-positive bacteria, such as Bacillus subtilis, which regulates many important biological processes. However, its functional essentiality remains largely unknown.

The O-antigen structure of bacterium Comamonas aquatica CJG.

Genus Comamonas is a group of bacteria that are able to degrade a variety of environmental waste. Comamonas aquatica CJG (C. aquatica) in this genus is able to absorb low-density lipoprotein but not high-density lipoprotein of human serum.

Conformational dynamics of the essential sensor histidine kinase WalK.

Two-component systems (TCSs) are key elements in bacterial signal transduction in response to environmental stresses. TCSs generally consist of sensor histidine kinases (SKs) and their cognate response regulators (RRs). Many SKs exhibit autokinase, phosphoryltransferase and phosphatase activities, which regulate RR activity through a phosphorylation and dephosphorylation cycle.

Oxidative stress affects retinal pigment epithelial cell survival through epidermal growth factor receptor/AKT signaling pathway.

Aim: To investigate the cross-talk between oxidative stress and the epidermal growth factor receptor (EGFR)/AKT signaling pathway in retinal pigment epithelial (RPE) cells.

Methods: Human RPE cell lines (ARPE-19 cell) were treated with different doses of epidermal growth factor (EGF) and hydrogen peroxide (HO). Cell viability was determined by a methyl thiazolyl tetrazolium assay.

Molecular Basis of Substrate Specific Acetylation by N-Terminal Acetyltransferase NatB.

The NatB N-terminal acetyltransferase specifically acetylates the N-terminal group of substrate protein peptides starting with Met-Asp/Glu/Asn/Gln. How NatB recognizes and acetylates these substrates remains unknown. Here, we report crystal structures of a NatB holoenzyme from Candida albicans in the presence of its co-factor CoA and substrate peptides.

Correction: Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway.

[This corrects the article DOI: 10.1371/journal.pone.

c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis.

It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis.

Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway.

Abnormal survival of retinal pigment epithelium (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR), a sight-threatening disease. In this study, we explored the effect of the anti-rheumatic agent auranofin (AF) on RPE cell survival and studied the underlying signaling mechanisms in vitro. Our results showed that AF inhibited ARPE-19 cell survival in a dose and time-dependent manner.

Draft Genome Sequence of the Bacterium Comamonas aquatica CJG.

A Gram-negative bacterial strain, Comamonas aquatica CJG, absorbs low-density lipoprotein but not high-density lipoprotein in serum. Here, we report its draft genomic sequence of 3,764,434 bp, containing total 3,425 genes, 27% of which encode proteins for metabolism and energy conversion, and it is 30% identical to the genome of Comamonas testosteroni.

Competitive Inhibition of Lysine Acetyltransferase 2B by a Small Motif of the Adenoviral Oncoprotein E1A.

The adenovirus early region 1A (E1A) oncoprotein hijacks host cells via direct interactions with many key cellular proteins, such as KAT2B, also known as PCAF (p300/CBP associated factor). E1A binds the histone acetyltransferase (HAT) domain of KAT2B to repress its transcriptional activation. However, the molecular mechanism by which E1A inhibits the HAT activity is not known.

Conformational Dynamics of Response Regulator RegX3 from Mycobacterium tuberculosis.

Two-component signal transduction systems (TCS) are vital for adaptive responses to various environmental stresses in bacteria, fungi and even plants. A TCS typically comprises of a sensor histidine kinase (SK) with its cognate response regulator (RR), which often has two domains-N terminal receiver domain (RD) and C terminal effector domain (ED). The histidine kinase phosphorylates the RD to activate the ED by promoting dimerization.

Histone cross-talk connects protein phosphatase 1α (PP1α) and histone deacetylase (HDAC) pathways to regulate the functional transition of bromodomain-containing 4 (BRD4) for inducible gene expression.

Transcription elongation has been recognized as a rate-limiting step for the expression of signal-inducible genes. Through recruitment of positive transcription elongation factor P-TEFb, the bromodomain-containing protein BRD4 plays critical roles in regulating the transcription elongation of a vast array of inducible genes that are important for multiple cellular processes. The diverse biological roles of BRD4 have been proposed to rely on its functional transition between chromatin targeting and transcription regulation.

Dimeric structure of p300/CBP associated factor.

Background: p300/CBP associating factor (PCAF, also known as KAT2B for lysine acetyltransferase 2B) is a catalytic subunit of megadalton metazoan complex ATAC (Ada-Two-A containing complex) for acetylation of histones. However, relatively little is known about the regulation of the enzymatic activity of PCAF.

Results: Here we present two dimeric structures of the PCAF acetyltransferase (HAT) domain.