Expanding the Organismal Proteostasis Network: Linking Systemic Stress Signaling with the Innate Immune Response
Jay Miles
Ruth Scherz-Shouval
Patricija van Oosten-Hawle
Open AccessPublished:July 11, 2019DOI:https://doi.org/10.1016/j.tibs.2019.06.009

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Highlights
Keywords
The Cellular and Organismal Proteostasis Network
Regulation of Stress Response Pathways in a Systemic Manner: The Search for the Cell-Non-autonomous Stress Signal
Innate Immune Response Signaling Pathways during Infection and Inflammation
Systemic Stress Signaling Pathways Regulating Innate Immunity
Innate Immune Pathways Regulating Organismal Proteostasis
Proteostasis and Immune Signals in Cancer
Concluding Remarks and Future Directions
Acknowledgements
References
Glossary
Article Info
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Highlights
Cellular stress response pathways, such as the heat shock response and unfolded protein responses in the endoplasmic reticulum and mitochondria, are regulated cell-non-autonomously via intercellular signaling processes.
Immune signals can be components of the expanded cell-non-autonomous proteostasis network that activate protein quality control mechanisms from one cell to another.
Transcellular chaperone signaling is a systemic proteostasis mechanism that requires transcellular signaling molecules such as neurotransmitters, neuropeptides, and immune effectors for the intercellular activation of protective chaperone expression.
The cell-non-autonomous co-ordination of proteostasis and immune responses is implicated in human pathological conditions including cancer.
Stress response pathways regulate proteostasis and mitigate macromolecular damage to promote long-term cellular health. Intercellular signaling is an essential layer of systemic proteostasis in an organism and is facilitated via transcellular signaling molecules that orchestrate the activation of stress responses across tissues and organs. Accumulating evidence indicates that components of the immune response act as signaling factors that regulate the cell-non-autonomous proteostasis network. Here, we review emergent advances in our understanding of cell-non-autonomous regulators of proteostasis networks in multicellular settings, from the model organism, Caenorhabditis elegans, to humans. We further discuss how innate immune responses can be players of the organismal proteostasis network and discuss how both are linked in cancer.
Keywords
proteostasis
stress responses
transcellular chaperone signaling
innate immune response
intercellular signaling
cancer
The Cellular and Organismal Proteostasis Network
The ability to maintain homeostasis in a dynamic environment is one of the most fundamental aspects of survival for all organisms. Each individual cell is a site of constant activity possessing rapid turnover of RNA, proteins, and other cellular components. As most cellular activities are performed by proteins, the maintenance of proteostasis (see Glossary) is a high priority. Because the function of each protein is determined by its structure, a functional proteome relies heavily on molecular chaperones, important components of the proteostasis network (PN) [1, 2]. Chaperones are vital for cellular and organismal physiology as they form core constituents of the translational machinery by assisting in co-translational folding at the ribosome [3]. Because of their importance for the PN, the ‘human chaperome’ comprises a vast network of 330 chaperone components, consisting of distinct gene families with different functions toward substrate proteins [4, 5]. Many chaperones are upregulated by robust stress response mechanisms to counteract protein misfolding and cellular damage imposed by proteotoxic stresses; such stresses include heat, oxidative stress, and pathogenic infections [6, 7, 8]. Another important aspect of the PN is the removal of misfolded or aggregated proteins by proteolytic degradation. This is accomplished by two major pathways: the ubiquitin proteasome system (UPS) and autophagy [9]. While the UPS is mainly responsible for targeting individual proteins to the proteasome, autophagy contributes to the clearance of large aggregates [9]. The UPS also interfaces with protein synthesis to remove defective nascent chains as part of the ribosomal quality-control pathways [10].
With the increasing complexity of multicellular organisms, regulation of stress responses and other protein quality control mechanisms relies on intercellular signaling pathways to systemically coordinate protein quality control processes across tissues and organs. This requires differential activation of appropriate tissue-specific PN components, as different cell types and tissues are characterized by their specific proteomes and different PN requirements [4, 11, 12]. Transcellular activation of stress responses is achieved by endo- and paracrine signaling pathways including hormones, cytokines, and other secreted peptides, as well as long-range neuroendocrine signaling mechanisms that are mediated via neurotransmitters and neuropeptides to induce protective transcriptional responses from one tissue to another [13, 14, 15, 16, 17].
The idea that cells and tissues experiencing proteotoxic stress communicate and transmit stress to other tissues is highly reminiscent of danger signals that activate immune defense responses across different cells [18] (Box 1). It also raises the question of whether intercellular immune signals used in the immune response could function as signaling components to mediate systemic proteostasis across tissues. Indeed, both immune responses and stress response pathways are tightly linked and can be activated by either proteotoxic stress or pathogen infection to provide cellular protection – a concept that was recognized early on in the field (Box 1) [19, 20, 21]. These intercellular protection mechanisms come at a cost, however. In cancer, both immune and stress responses are hijacked to promote survival of cells in the stressful tumor microenvironment [22, 23, 24, 25, 26].
Box 1
Linking Stress Response and Immune Response Mechanisms: Of DAMPS, Extracellular Chaperones, and Cytokines
Stress responses and immune responses are different, yet share striking similarities. While immune responses are specifically designed to target foreign molecules and pathogens in an organism, cellular stress response mechanisms generally act to promote and maintain proteostasis in response to environmental stress or chronic intracellular stress conditions that challenge the integrity of the cellular proteome. The fact that both are connected and more closely related than they first appeared was recognized in the 1990s by several observations. For example, cells exposed to heat shock prior to pathogenic infection are protected against the consequences of pathogenic infection, due to increased levels of the heat-inducible Hsp72 chaperone [133]. Later on, the discovery that HSPs such as Hsp70 and Hsp60 also exist extracellularly [134, 135] led to the realization that HSPs are also modulators of the immune system by regulating the production and secretion of immunoregulatory cytokines [86, 87, 131]. Cytokines are a large group of small proteins facilitating paracrine and autocrine intercellular signalling processes that have been associated with immunity and inflammation [136]. They are induced by PAMPs as a first line of response to pathogenic microbial infections. In 2002, Polly Matzinger described the concept of danger signals in the immune response as a mechanism to respond to danger molecules such as free radicals, nucleotides, pathogens, and HSPs among many others [