Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling - PubMed (original) (raw)

Review

Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling

Patricija van Oosten-Hawle et al. Genes Dev. 2014.

Abstract

Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span.

Keywords: C. elegans; chaperones; proteostasis; stress response; transcellular stress signaling.

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Figures

Figure 1.

Transcellular chaperone signaling in the regulation of systemic proteostasis. (A) Local overexpression of HSP90 represses the HSR cell-nonautonomously during heat stress, as shown by expression of an hsp70 reporter. (B) Model for transcellular chaperone signaling through tissue-specific overexpression of HSP90. Increased expression of HSP90 in the sender tissue potentially activates PHA-4. PHA-4-dependent expression of transcellular stress factors (TSFs) is transmitted from the sender cell to specific receiving cells, where PHA-4-dependent expression of, e.g., hsp90 is initiated. (C) Tissue-specific reduction of hsp90 expression through hsp90 hairpin RNAi (hp-hsp90) induces the HSR (hsp70 reporter) cell-nonautonomously in different tissues at the permissive temperature. (D) Model for transcellular chaperone signaling through reduction of hsp90 expression in the sender tissue. Reduced availability of hsp90 in the sender cell activates HSF-1 transcriptional activity in the sender cell. A TSF, potentially dependent on HSF-1 transcription, is secreted from the sender tissue and taken up by specific receiving tissues, where it initiates HSF-1 activity and transcription of HSPs. (m) Body wall muscle; (int) intestine. Figures adapted from van Oosten-Hawle et al. (2013), © 2013, with permission from Elsevier.

Figure 2.

Intertissue signaling mechanisms integrating organismal proteostasis. (A) Direct signaling between nonneuronal tissues. An imbalanced PN in the sender tissue triggers activation of transcription factors and corresponding expression of signaling molecules or TSFs. TSFs are potentially secreted and taken up by receiving tissues through cellular junctions and transmembrane channels or by binding to specific receptors, which initiates a responsive signaling cascade in the receiving cell and activates a transcriptional program to increase the expression of PQN components required for stress resistance. (B) Indirect signaling between nonneuronal tissues via a neural feedback. An imbalanced PN in a nonneuronal sender tissue is signaled in a feedback response to the nervous system (i.e., estrogen signaling), which activates specific neuroendocrine signaling pathways to rapidly change transcriptional programs in peripheral nonneuronal tissues.

Figure 3.

Secreted signaling molecules in the regulation of proteostasis via the nervous system and through paracrine communication between nonneuronal somatic tissues. Neurons perceive environmental stimuli and integrate the environmental challenge to fine-tune proteostasis in peripheral tissues through neuronally synthesized neuropeptides, neurotransmitters, and hormones. Nonneuronal tissues such as gonad, intestine, or muscle tissue communicate independently of neural control via autocrine/paracrine and endocrine activities with each other and can also report altered proteostasis conditions back to the nervous system.

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Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling - PubMed (original) (raw)