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

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.

Sir2 links the unfolded protein response and the heat shock response in a stress response network

“…This inter-organellar cell-autonomous stress response network is reminiscent of the looming cell-nonautonomous transcellular signaling that coordinates stress responses between tissues [30,31]. This systemic cellular regulation of stress responses is supported by a genome-wide comparison of 383 UPR-and 165 HSR-regulated genes [25,32], where at least nine genes, common to both data sets, appear to be regulated by both UPR and HSR [24].…”

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…AD‐enriched aggregates include proteins associated with heat‐shock and unfolded protein responses, inflammation, and/or innate immunity—categories previously shown to be associated with aging (Finch et al ., 2010; van Oosten‐Hawle & Morimoto, 2014). Examples include ApoE, complement C3, chaperones (e.g., HSP70.2), plectin, ATP‐dependent RNA helicases, BM‐specific heparin sulfate, filamins A and C, lamin A/C, laminin, talin, tenascins, and vinculin.…”

Proteotoxicity and Cardiac Dysfunction

“…1 The chaperones are represented by multiple classes and have diverse natures. 41 Their many functional roles are underscored by changes they may undergo as a result of post-translational modification, 42 the potential for their trans-cellular activities 43 and the role they play in a wide variety diseases including but not limited to Pompe disease, Huntington disease, cancer, pulmonary and cardiovascular disease. 6,44-51 Not surprisingly, considering their role in these processes, targeting the chaperones has become a legitimate therapeutic avenue.…”