Chemical engineering of bacterial effectors for regulating cell signaling and responses

Bacteria have evolved a variety of effector proteins to facilitate their survival and proliferation within the host environment. Continuous competition at the host–pathogen interface has empowered these effectors with unique mechanism and high specificity toward their host targets. The rich repertoire of bacterial effectors has thus provided us an attractive toolkit for investigating various cellular processes, such as signal transductions. With recent advances in protein chemistry and engineering, we now have the capability for on-demand control of protein activity with high precision. Herein, we review the development of chemically engineered bacterial effectors to control kinase-mediated signal transductions, inhibit protein translation, and direct genetic editing within host cells. We also highlight future opportunities for harnessing diverse prokaryotic effectors as powerful tools for mechanistic investigation and therapeutic intervention of eukaryotic systems.     

Intercepting host MAPK signaling cascades by bacterial type III effectors

The evolutionarily conserved MAP kinase (MAPK) cascades play essential roles in plant and animal innate immunity. A recent explosion of research has uncovered a myriad of virulence strategies used by pathogenic bacteria to intercept MAPK signaling through diverse type III effectors injected into host cells. Here, we review the latest literature and discuss the various mechanisms that pathogenic bacteria use to manipulate host MAPK signaling cascades.     

Eukaryotic cell signaling and transcriptional activation induced by bacterial porins

The protein composition of the outer membrane of Gram-negative bacteria consists of about 20 immunochemically distinct proteins, termed outer membrane proteins (OMPs). Apart from their structural role, OMPs have been shown to have other functions, particularly with regard to transport, and have been classified as permeases and porins. Porins, during their interaction with the host, are immunogenic and also directly stimulate several cellular functions. Porins work both as molecules present on the bacterial surface and as molecules released by bacteria. Lipopolysaccharide and OMPs, the major structural macromolecular constituents of the outer membrane, carry out a fundamental role in the pathogenesis of Gram-negative infections. This brief review describes the multiple facets of the biological activities of porins both in vitro and in vivo, particularly focusing on their ability to induce the expression of cytokines and other factors that modulate cellular activities with either pathological or adaptive consequences. This brief discussion will focus on the signal transmission mechanisms induced by bacterial porins.     

Sabotage of antiviral signaling and effectors by influenza viruses

Vertebrate cells activate multiple signaling modules upon virus infection to eliminate the invading pathogen and to prevent the establishment of a persistent infection. A major immediate response pathway is controlled by the RNA helicases RIG-I and MDA5, which, after recognition of viral nucleic acids, signal induction of the interferon (IFN)-alpha/beta cytokine family that upregulates numerous antiviral effector proteins. Virulent viruses, in contrast, have learned during co-evolution with their hosts to manipulate or avoid this response in order to prevail in a repulsive environment. Focusing on the influenza viruses and their IFN-antagonistic NS1 proteins, we summarize recent progress in this rapidly evolving field at the intersection of virology and immunobiology involving studies of how viral pathogens induce and sabotage cellular defenses.     

Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle

Microbial pathogens have developed a variety of strategies to manipulate host-cell functions, presumably for their own benefit. We propose the term "cyclomodulins" to describe the growing family of bacterial toxins and effectors that interfere with the eukaryotic cell cycle. Inhibitory cyclomodulins, such as cytolethal distending toxins (CDTs) and the cycle inhibiting factor (Cif), block mitosis and might constitute powerful weapons for immune evasion by inhibiting clonal expansion of lymphocytes. Cell-cycle inhibitors might also impair epithelial-barrier integrity, allowing the entry of pathogenic bacteria into the body or prolonging their local existence by blocking the shedding of epithelia. Conversely, cyclomodulins that promote cellular proliferation, such as the cytotoxic necrotizing factor (CNF), exemplify another subversion mechanism by interfering with pathways of cell differentiation and development. The role of these cyclomodulins in bacterial virulence and carcinogenesis awaits further study and will delineate new perspectives in basic research and therapeutic applications.     

病原菌效应因子调控宿主泛素化修饰的研究进展北大核心

泛素化(ubiquitination)是真核细胞内广泛存在的蛋白质翻译后修饰方式,参与并调控DNA修复、细胞周期、免疫应答、信号通路等真核细胞内几乎所有的生命活动。同时,细胞通过去泛素化酶(deubiquitinases,DUBs)使泛素化修饰成为可逆过程,保证了泛素化系统及其相关生理过程的动态平衡。病原菌感染过程中,宿主细胞可通过泛素化修饰发挥抗细菌感染作用。然而,病原菌可编码并分泌效应因子,靶向宿主泛素(ubiquitin,Ub)系统并调控宿主泛素化修饰过程,干扰宿主细胞的免疫应答,从而促进细菌存活与毒力。本文概述了重要病原菌利用效应因子调控宿主细胞泛素化修饰的研究进展,有助于全面理解病原菌调控宿主泛素化修饰促进感染的机制。     

Co-evolution and exploitation of host cell signaling pathways by bacterial pathogens

Bacterial pathogens have evolved by combinations of gene acquisition, deletion, and modification, which increases their fitness. Additionally, bacteria are able to evolve in quantum leaps via the ability to promiscuously acquire new genes. Many bacterial pathogens - especially Gram-negative enteric pathogens - have evolved mechanisms by which to subvert signal transduction pathways of eukaryotic cells by expressing genes that mimic or regulate host protein factors involved in a variety of signaling cascades. This results in the ability to cause diseases ranging from tumor formation in plants to gastroenteritis and bubonic plague. Here, we present recent advances on mechanisms of bacterial pathogen evolution, including specific signaling cascades targeted by their virulence genes with an emphasis on the ubiquitin modification system, Rho GTPase regulators, cytoskeletal modulators, and host innate immunity. We also comment briefly on evolution of host defense mechanisms in place that limit disease caused by bacterial pathogens.     

Collaborative signaling by bacterial chemoreceptors

Motile bacteria seek optimal living habitats by following gradients of attractant and repellent chemicals in their environment. The signaling machinery for these chemotactic behaviors, although assembled from just a few protein components, has extraordinary information-processing capabilities. Escherichia coli, the best-studied model, employs a networked cluster of transmembrane receptors to detect minute chemical stimuli, to integrate multiple and conflicting inputs, and to generate an amplified output signal that controls the cell's flagellar motors. Signal gain arises through cooperative action of chemoreceptors of different types. The signaling-teams within a receptor cluster may be built from trimers of receptor dimers that communicate through shared connections to their partner signaling proteins.     

Host-pathogen interplay and the evolution of bacterial effectors

Many bacterial pathogens require a type III secretion system (T3SS) and suite of type III secreted effectors (T3SEs) to successfully colonize their hosts, extract nutrients and consequently cause disease. T3SEs, in particular, are key components of the bacterial arsenal, as they function directly inside the host to disrupt or suppress critical components of the defence network. The development of host defence and surveillance systems imposes intense selective pressures on these bacterial virulence factors, resulting in a host–pathogen co-evolutionary arms race. This arms race leaves its genetic signature in the pattern and structure of natural genetic variation found in T3SEs, thereby permitting us to infer the specific evolutionary processes and pressures driving these interactions. In this review, we summarize our current knowledge of T3SS-mediated host–pathogen co-evolution. We examine the evolution of the T3SS and the T3SEs that traverse it, in both plant and animal pathosystems, and discuss the processes that maintain these important pathogenicity determinants within pathogen populations. We go on to examine the possible origins of T3SEs, the mechanisms that give rise to new T3SEs and the processes that underlie their evolution.     

Evolutionarily conserved bacterial effectors hijack abscisic acid signaling to induce an aqueous environment in the apoplast

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Biochemistry of transmembrane signaling mediated by trimeric G proteins

Many extracellular signals are at the cell surface received by specific receptors, which upon activation transduce information to the appropriate cellular effector molecules via trimeric G proteins. The G protein-mediated cascades ultimately lead to the highly refined regulation of systems such as sensory perception, cell growth, and hormonal regulation. Transmembrane signaling may be seriously deranged in various pathophysiological conditions. Over the last two decades the major experimental effort of our group has been devoted to better understanding the molecular mechanisms underlying transmembrane signaling regulated by G proteins and to the closely related process of desensitization of hormone response. This review provides general information about the basic principles of G protein-regulated transmembrane signaling as well as about our contribution to the current progress in the field.