Bacteria live in diverse and variable environments and constitute about half of the world's biomass. Free-living bacteria must adapt to daily and seasonal temperature changes;those living in host organisms experience temperature change during their transmission cycles, which usually include transient residence in the external environment (e.g. fecal-oral transmission). On the other hand, 90% of the oceans are ? 5?C, adaptations that enable bacterial growth in the cold are essential for many bacteria. In toto, adaptation to temperature change is one of the most pervasive challenges facing bacteria. We study the stress responses that enable adaptation to both heat and cold. Our long-term studies of thermal adaptation have consistently set new paradigms. We identified and are dissecting the two homeostatic circuits that monitor protein folding in all compartments of the bacterial cell. ?3 monitors both cytoplasmic and inner membrane (IM) protein folding status, whereas ?E monitors protein-folding stress in the envelope, and maintains outer membrane (OM) homeostasis, serving as a paradigm for intercompartmental communication in prokaryotes. Thus, we have identified and are studying the central protein quality control circuitry of gram-negative bacteria It is the underlying mechanisms and principles of process coordination that is the focus of our new studies. We will determine how the circuitry controlling s32 integrates protein folding status signals from both the IM and cytoplasmic compartment. Likewise, we will investigate how the circuitry controlling ?32 integrates three signals of OM homeostasis. Higher order process integration is poorly understood in any organism. Importantly, the existing knowledge base and available tools permit us to carry out an incisive investigation of this critical issue. Additionaly, these studies may provide the first example of how unicellular organisms sense and integrate signals from their outer membranes or cell walls to maintain cellular integrity. In contrast to hea shock responses that are mediated by transcriptional homeostatic circuits, cold adaptation is centered around how the cell responds to critical failures in translation. This response is poorly understood, despite its universality. As cold shock perturbs central gene expression processes, it may expose critical, unanticipated interconnections between these processes. We study the cold shock response using a revolutionary new technology that enables us to detect instantaneous changes in translation at the genomic level with great sensitivity and near-nucleotide resolution. Our initial results modifying this technique for the bacterial CSR not only immediately identified the temporal pattern of the response but also revealed unexpected changes in global translational pausing and termination that were inaccessible by previous methods, thereby increasing the known repertoire of translational modulation. We will continue to dissect the process interconnections we have identified and also perform comparable studies in B. subtilis, to uncover common and unique strategies to this universal stress.

Public Health Relevance

Bacteria live in diverse and variable environments, and must adapt to daily and seasonal changes in temperature to be successful. Understanding the processes used to mediate adaptation to heat and cold is an important area of study. On the one hand, it will enable us to develop new strategies to fight disease. On the other hand, once the critical circuits are identified, we may be able to alter them to enable bacteria to live in ne environments, which may be necessary as the plant warms.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Prokaryotic Cell and Molecular Biology Study Section (PCMB)
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Reddy, Michael K
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University of California San Francisco
Schools of Medicine
San Francisco
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Zhang, Yan; Burkhardt, David H; Rouskin, Silvi et al. (2018) A Stress Response that Monitors and Regulates mRNA Structure Is Central to Cold Shock Adaptation. Mol Cell 70:274-286.e7
Baggett, Natalie E; Zhang, Yan; Gross, Carol A (2017) Global analysis of translation termination in E. coli. PLoS Genet 13:e1006676
Burkhardt, David H; Rouskin, Silvi; Zhang, Yan et al. (2017) Operon mRNAs are organized into ORF-centric structures that predict translation efficiency. Elife 6:
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