Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons

Abstract

Temperature pervasively affects all cellular processes. In response to a rapid increase in temperature, all cells undergo a heat shock response, an ancient and highly conserved program of stress-inducible gene expression, to reestablish cellular homeostasis. In isolated cells, the heat shock response is initiated by the presence of misfolded proteins and therefore thought to be cellautonomous. In contrast, we show that within the metazoan Caenorhabditis elegans, the heat shock response of somatic cells is not cell-autonomous but rather depends on the thermosensory neuron, AFD, which senses ambient temperature and regulates temperature-dependent behavior. We propose a model whereby this loss of cell autonomy serves to integrate behavioral, metabolic, and stress-related responses to establish an organismal response to environmental change.The heat shock response counteracts the detrimental effects of protein misfolding and aggregation that result from biochemical and environmental stresses, including increases in temperature (1, 2). This response, orchestrated by the ubiquitously expressed heat shock factor-1 (HSF-1), involves the rapid transcription of a specific set of genes encoding the cytoprotective heat shock proteins (HSPs) (1, 2). The stress-induced appearance of nonnative proteins imbalances cellular homeostasis, and the resulting shift in chaperone requirements is thought to trigger the heat shock response (1, 2). Because all these events occur at the cellular level, the heat shock response is thought to be cell-autonomous. Indeed, isolated cells in tissue culture, unicellular organisms (1, 2), and individual cells within a multicellular organism (3) can all produce a heat shock response when exposed directly to heat.Although the heat shock response is essential for the survival of cells exposed to stress, the accumulation of large amounts of HSPs can be detrimental for cell growth and division (2, 4). Therefore, although cellular autonomy in initiating this response may be beneficial for unicellular organisms and isolated cells, the uncoordinated triggering of the heat shock response in individual cells within a multicellular organism could interfere with the complex interactions between differentiated cells and tissues.In Caenorhabditis elegans, a pair of thermosensory neurons, the AFDs, detect and respond to ambient temperature (5, 6). The AFDs, and their postsynaptic partner cells, the AIYs, regulate the temperature-dependent behavior of the organism and are required for finding * To whom correspondence should be addressed. r-morimoto@northwestern.edu. the optimal temperature for growth and reproduction (6). We tested whether this thermosensory neuronal circuitry also regulates the heat shock response of somatic cells. For this, we exposed wild-type C. elegans or animals carrying loss-of-function mutations affecting the AFD or AIY neurons (Fig. 1A) to a transient increase in temperature and assayed their heat shock response. The mutations chosen {gcy-23, gcy-8 (7), tax-4, ttx-1, and ttx-3 [fo...

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