Transcellular chaperone signaling: an organismal strategy for integrated cell stress responses

Abstract

The ability of each cell within a metazoan to adapt to and survive environmental and physiological stress requires cellular stress-response mechanisms, such as the heat shock response (HSR). Recent advances reveal that cellular proteostasis and stress responses in metazoans are regulated by multiple layers of intercellular communication. This ensures that an imbalance of proteostasis that occurs within any single tissue 'at risk' is protected by a compensatory activation of a stress response in adjacent tissues that confers a community protective response. While each cell expresses the machinery for heat shock (HS) gene expression, the HSR is regulated cell non-autonomously in multicellular organisms, by neuronal signaling to the somatic tissues, and by transcellular chaperone signaling between somatic tissues and from somatic tissues to neurons. These cell non-autonomous processes ensure that the organismal HSR is orchestrated across multiple tissues and that transmission of stress signals between tissues can also override the neuronal control to reset cell- and tissue-specific proteostasis. Here, we discuss emerging concepts and insights into the complex cell non-autonomous mechanisms that control stress responses in metazoans and highlight the importance of intercellular communication for proteostasis maintenance in multicellular organisms.

Keywords: Caenorhabditis elegans; Cell non-autonomous; Chaperones; Metazoans; Proteostasis; Stress response.

Fig. 1.

Cell non-autonomous control of the heat shock response (HSR) by neurons. Organismal control of heat shock transcription factor 1 (HSF-1) transcriptional activity in peripheral tissues by the thermosensory AFD neuron via a guanylyl cyclase GCY-8-dependent signaling cascade. A steroid signalling-dependent feedback loop from peripheral cells reports HSR activity back to the AFD neurons.

Fig. 2.

Transcellular chaperone signaling regulates the organismal HSR via tissue-to-tissue crosstalk. An imbalance of proteostasis in a single tissue, through reduced (orange) or elevated (blue) expression of Hsp90, is detected and responded to in a different tissue via transcellular chaperone signaling. Because of the key role of Hsp90 as a negative regulator of the HSF-1-dependent HSR, the HSR is either induced (orange) or repressed (blue) at a cell non-autonomous level, leading to different outcomes for organismal survival during stress conditions.

Fig. 3.

Cell non-autonomous control of proteostasis via the nervous system and transcellular chaperone signaling. Sensory neurons perceive environmental stimuli and integrate the environmental challenge to fine-tune proteostasis in peripheral tissues. Non-neuronal tissues report altered proteostasis conditions back to the nervous system. At the same time, tissue-to-tissue signals via transcellular chaperone signaling can override the neuronal component to control cell-specific proteostasis. This allows proteostasis crosstalk between somatic cells independent of neural control.