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1.
Science ; 370(6518): 853-856, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33184215

RESUMO

Shutoff of global protein synthesis is a conserved response to cellular stresses. This general phenomenon is accompanied by the induction of distinct gene programs tailored to each stress. Although the mechanisms driving repression of general protein synthesis are well characterized, how cells reprogram the translation machinery for selective gene expression remains poorly understood. Here, we found that the noncanonical 5' cap-binding protein eIF3d was activated in response to metabolic stress in human cells. Activation required reduced CK2-mediated phosphorylation near the eIF3d cap-binding pocket. eIF3d controls a gene program enriched in factors important for glucose homeostasis, including members of the mammalian target of rapamycin (mTOR) pathway. eIF3d-directed translation adaptation was essential for cell survival during chronic glucose deprivation. Thus, this mechanism of translation reprogramming regulates the cellular response to metabolic stress.


Assuntos
Fator de Iniciação 3 em Eucariotos/biossíntese , Glucose/deficiência , Biossíntese de Proteínas , Estresse Fisiológico , Adaptação Fisiológica , Sobrevivência Celular , Fator de Iniciação 3 em Eucariotos/genética , Células HEK293 , Humanos , Fosforilação , Serina-Treonina Quinases TOR/metabolismo
2.
PLoS Genet ; 14(10): e1007714, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30346960

RESUMO

Two-component signaling systems (TCS) regulate bacterial responses to environmental signals through the process of protein phosphorylation. Specifically, sensor histidine kinases (SK) recognize signals and propagate the response via phosphorylation of a cognate response regulator (RR) that functions to initiate transcription of specific genes. Signaling within a single TCS is remarkably specific and cross-talk between TCS is limited. However, regulation of the flow of information through complex signaling networks that include closely related TCS remains largely unknown. Additionally, many bacteria utilize multi-component signaling networks which provide additional genetic and biochemical interactions that must be regulated for signaling fidelity, input and output specificity, and phosphorylation kinetics. Here we describe the characterization of an NtrC-like RR that participates in regulation of Type-IV pilus-dependent motility of Myxococcus xanthus and is thus named NmpR, NtrC Modulator of Pili Regulator. A complex multi-component signaling system including NmpR was revealed by suppressor mutations that restored motility to cells lacking PilR, an evolutionarily conserved RR required for expression of pilA encoding the major Type-IV pilus monomer found in many bacterial species. The system contains at least four signaling proteins: a SK with a protoglobin sensor domain (NmpU), a hybrid SK (NmpS), a phospho-sink protein (NmpT), and an NtrC-like RR (NmpR). We demonstrate that ΔpilR bypass suppressor mutations affect regulation of the NmpRSTU multi-component system, such that NmpR activation is capable of restoring expression of pilA in the absence of PilR. Our findings indicate that pilus gene expression in M. xanthus is regulated by an extended network of TCS which interact to refine control of pilus function.


Assuntos
Proteínas de Fímbrias/genética , Fímbrias Bacterianas/metabolismo , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Histidina Quinase/genética , Myxococcus xanthus/genética , Fosforilação , Transdução de Sinais , Supressão Genética , Fatores de Transcrição/genética
3.
Mol Microbiol ; 102(1): 37-53, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27393239

RESUMO

Myxococcus xanthus is an environmental bacterium with two forms of motility. One type, known as social motility, is dependent on extension and retraction of Type-IV pili (T4P) and production of extracellular polysaccharides (EPS). Several signaling systems have been linked to regulation of T4P-dependent motility. In particular, expression of the pilin subunit pilA requires the PilSR two-component signaling system (TCS). A second TCS, PilS2R2, encoded within the same locus that encodes PilSR, has also been linked to M. xanthus T4P-dependent motility. We demonstrate that PilSR and PilS2R2 regulate M. xanthus T4P-dependent motility through distinct pathways. Consistent with known roles of PilSR, our results indicate that the primary function of PilSR is to regulate expression of pilA. In contrast, PilS2 and PilR2 have little to no affect on PilA protein levels. However, deletion of pilR2 resulted in a reduction of assembled pili, significant decreases in EPS production and loss of T4P-dependent motility. Furthermore, the pilR2 mutation led to increased production of outer membrane vesicles (OMV). Collectively, we propose that PilS2R2 is required for proper assembly of T4P and regulation of OMV production, and hypothesize that production of these vesicles is related to M. xanthus motility.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Fímbrias/metabolismo , Myxococcus xanthus/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Proteínas de Fímbrias/genética , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/metabolismo , Mutação , Myxococcus xanthus/genética , Fatores de Transcrição/genética
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