Rice Institute for Biomedical Research
Department of Molecular Biosciences
Proteostasis, at the organismal level, has multiple layers of regulatory control required by the complex requirements of highly specialized tissues that express distinct proteomes (Sala et al., 2017). For example, muscle and neurons express proteomes with different requirements and properties, therefore the risk for damage from an imbalanced proteome may not be the same. The highly abundant myofilament proteins titan and myosin are expressed at millions of copies per muscle cell, consequently, errors in folding stability generated by polymorphisms or mutations could generate a disproportionate number of damaged molecules that are resolved when the Proteostasis Network is robust but could overwhelm the capacity of the quality control machinery during aging (Labbadia et al., 2015). To compensate for such an imbalance, metazoans employ intertissue communication to ensure that proteome failure within a single tissue does not cause organismal failure (Morimoto, 2019).
Veena Prahlad demonstrated that the heat shock response (HSR) is regulated cell non-autonomously by specific sensory neurons in C. elegans (Prahlad et al. 2008). Mutations in the AFD thermosensory or connected interneurons rendered animals deficient selectively for induction of the HSR by heat shock, but did not interfere with the HSF1-dependent induction of heat shock gene expression using a different cell stress condition corresponding to the heavy metal cadmium (Prahlad et al. 2008). The regulation of the HSR involves calcium-activated dense core vesicles (DCV) that is mediated by serotonergic signaling (Prahlad and Morimoto 2011; Tatum et al. 2015). This was further demonstrated by Veena using optogenetic activation of thermosensory or serotonergic neurons that activated the HSR in the absence of heat shock stress in nonneuronal somatic tissues, thus providing direct evidence that serotonin is a mediator of tissue communication in the regulation of the HSR (Tatum et al. 2015). Serotonin couples stress sensing and neurotransmitter activity with movement, fecundity, and the response to food (Tatum et al. 2015). Animals deficient for AFD signaling, while lacking the organismal coordination of the HSR, remain competent at the cellular level to induce the expression of molecular chaperones of the HSP70 and small HSP family cell-autonomously in response to tissue specific expression of polyQ aggregates (Prahlad and Morimoto 2011). From these studies, we proposed that AFD signaling, while conferring centralized control of the HSR, also provides a reversible switch that shifts the animal from cell-nonautonomous to cell-autonomous control. The cell-autonomous induction of chaperone expression in tissues chronically expressing aggregation-prone proteins indicate that C. elegans employs different tissue and signaling networks to respond to acute forms of environmental stress such as heat shock and to the chronic expression of damaged proteins.
Another role for neuronal control of ORGANISMAL PROTEOSTASIS was identified in genetic screens for suppressors and enhancers of polyQ aggregation performed by Susana Garcia and by Catarina Silva (Garcia et al. 2007; Silva et al. 2011; 2013). Susana used a forward genetic screen for enhancers of polyQ35 aggregation expressed in muscle cells and identified a mutation in GABA expressed in neurons that compromised muscle cell proteostasis (Garcia et al. 2007). Catarina performed a complementary reverse genetic genome-wide RNAi screen to identify suppressors of polyQ35 aggregation and identified a regulator of the acetylcholine receptor expressed in muscle cells that enhanced proteostasis (Silva et al. 2011, 2013). The stimulation of cholinergic signaling increased Ca2+ flux in the muscle cells, activating calmodulin and Ca-dependent kinases that activated HSF-1 activity and the expression of cytoplasmic chaperones (Silva et al. 2013). Together, the results of these genetic screens reveal how neurons communicate through neurotransmitters to regulate proteostasis.
A distinct and complementary form of intertissue communication was identified by Patricija van Oosten-Hawle who observed in C. elegans expressing a muscle specific temperature-sensitive (TS) myosin that the Hsp90p::GFP reporter was induced both in muscle cells and in other tissues that do not express myosin (van Oosten-Hawle et al. 2013). Transcellular chaperone signaling of Hsp90 was shown to be regulated by the tissue code factor, PHA4/FOXA. Consistent with a proposed role for transcellular chaperone signaling, suppression of the myosin TS folding and motility defect was obtained by overexpression of Hsp90 in muscle cells, but equally when Hsp90 was overexpressed in the intestine and neurons. These regulated events had beneficial consequences on organismal proteostasis and stress resilience, suggesting that individual tissues within an organism can serve as sensors that respond to local disruptions in proteostasis, and as sentinels to disseminate local stress proteotoxic signals to other tissues to mount an organismal protective response (van Oosten- Hawle and Morimoto 2014).
Another line of evidence in which the PROTEOSTASIS NETWORK and THE HEAT SHOCK RESPONSE are regulated by cell-nonautonomous control come from studies on aging. Anat Ben-Zvi following on work with Tali Gidalevitz (Gidalevitz, Ben-Zvi et al., 2006) showed that temperature-sensitive metastable proteins misfold at the permissive temperature during C. elegans aging (Ben-Zvi et al., 2009). The decline in the organismal HSR in early adulthood of C. elegans occurs at reproductive maturity and is regulated by signals from the germline stem cells (Labbadia and Morimoto 2015). Repression of the HSR involves the placement of the repressive H3K27me3 chromatin marks and reduced chromatin accessibility at the promoters of genes encoding HSPs and the UPR, thus leaving the adult animal susceptible to environmental stress conditions. The timing of the repression of the HSR at reproductive maturity presumably is selected by energy and resource allocation and represents among the earliest molecular events of aging.
Ben-Zvi-A., E.A. Miller, and R.I. Morimoto. The Collapse of Proteostasis Represents an Early Molecular Event in C. elegans Aging. Proc. Natl. Acad. Sci. USA 106: 14914-14919. (2009).
Brignull, H.R., J.F. Morley, S.M. Garcia, and R.I. Morimoto. Modeling Polyglutamine Pathogenesis in C. elegans. Methods in Enzymology 412: 256-282. (2006).
Brignull, H., F. Moore, S. Tang, and R. I. Morimoto. Polyglutamine Proteins at the Pathogenic Threshold Display Neuron-Specific Aggregation in a Pan-Neuronal Caenorhabditis elegans Model. The Journal of Neuroscience 26(29): 7597-7606. (2006).
Garcia, S. M., M.O. Casanueva, M.C. Silva, M.D. Amaral, and R.I. Morimoto,, Neuronal signaling modulates protein homeostasis in C. elegans postsynaptic muscle cells. Genes and Development 21: 3006-3016. (2007).
Gidalevitz, T., A. Ben-Zvi, K. Ho, H. Brignull, and R. I. Morimoto. Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases. Science 311: 1471-1474. (2006).
Gidalevitz, T., T. Krupinski, S. Garcia, and R.I. Morimoto. Destabilizing Protein Polymorphisms in the Genetic Background Direct Phenotypic Expression of Mutant SOD1 Toxicity. PLoS Genet 5(3): e1000399 (2009).
Gidalevitz, T., V. Prahlad, and R. I. Morimoto. The Stress of Protein Misfolding: From Single Cells to Multicellular Organisms. Cold Spring Harbor Perspectives in Biology 3. PMID: 21536706 (2011).
Kikis, E.A., A. Ben-Zvi, and R.I. Morimoto. C. elegans as a Model System to Study the Biology of Protein Aggregation and Toxicity. In: Protein Misfolding Diseases: Current and Emerging Principles and Therapies (Edited by M. Ramirez-Alvarado, J. Kelly, and C. Dobson), p. 175-190, Wiley Press (2010).
Kirstein, J., D. Morito, T. Kakihana, M. Sugihara, A. Minnen, M.S. Hipp, C. Nussbaum-Krammer, F.U. Hartl, K. Nagata, and R.I. Morimoto. Proteotoxic Stress and Ageing Triggers the Loss of Redox Homeostasis Across Cellular Compartments. EMBO Journal 34: 2334-2349. PMID:26228940 (2015).
Krammer, C., K.W. Park, L. Li, R. Melki, and R.I. Morimoto. Spreading of a Prion Domain from Cell to Cell by Vesicular Transport in C. elegans. PLoS Genetics 9(3). DOI: 10.1371, PMID: 23555277 (2013).
Labbadia, J., R. Brielmann, M. Neto, Y.-F. Lin, C.M. Haynes, and R.I. Morimoto. Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse During Aging. Cell Reports 21: 1481-1494, DOI.org/10.1016/ j.celrep.2017.10.038 (2017).
Labbadia, J. and R.I. Morimoto. Repression of the Heat Shock Response is a Programmed Event at the Onset of Reproduction. Molecular Cell 59: 639-650, DOI 10.1016/j. molcel.2015.06.027 PMID: 266212459 (2015).
Morimoto, R.I. Cell Non-Autonomous Regulation of Proteostasis in Aging and Disease. Cold Spring Harbor Perspectives in Biology. DOI: 10.1101/cshperspect.a034074 (2019).
Morimoto, R.I. Stress, Aging and Neurodegenerative Disease. The New England Journal of Medicine 355(21): 2254-2255 (2006).
Morley J.F., Brignull H.R., Weyers J.J., Morimoto R.I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci USA. (2002).
Morley, J.F. and Morimoto, R. Regulation of Longevity in Caenorhabditis elegans by Heat Shock Factor and Molecular Chaperones. Mol Biol Cell. Feb;15: 657-64. (2004).
Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, Morimoto RI, Plasterk RH. Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci USA, 101: 6403-6408. (2004).
Nussbaum-Krammer, C., and R.I. Morimoto. Caenorhabditis elegans as a Model System for Cell Non-Autonomous Mechanisms in Protein Misfolding Diseases. Disease Models and Mechanisms 7: 31-39. DOI: 10.1242, PMID: 24396152 (2014).
Prahlad, V., T. Cornelius and R.I. Morimoto, . Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons. Science 320: 811-814. (2008).
Prahlad, V., and R.I. Morimoto. Integrating the Stress Response: Lessons for Neurodegenerative Diseases from C. elegans. Trends in Cell Biology 19: 52-61. (2009). [2008 Dec 26 Epub ahead of print]. PMID: 19112021 [PubMed – as supplied by publisher].
Prahlad, V. and R.I. Morimoto. Neuronal Circuitry Regulates the Response of C. elegans to Misfolded Proteins. Proc. Natl. Acad. Sci. U.S.A. 108: 14204-14209. PMID: 1106557108 (2011).
Sala, A.J., L.C. Bott, and R.I. Morimoto. Shaping Proteostasis at the Cellular, Tissue, and Organismal Level. Journal of Cell Biology 216. DOI: 10.1083/jcb.201612111 (2017).
Sala, A.J., L.C. Bott, R.M. Brielmann, and R.I. Morimoto. Embryo Integrity Regulates Maternal Proteostasis and Stress Resilience. Genes and Development 34: 678-687. doi:10.1101/gad.335422.119, PMID: 32217667 (2020).
Satyal SH, Schmidt E, Kitagawa K, Sondheimer N, Lindquist S, Kramer JM, Morimoto RI. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc Natl Acad Sci USA 23; 97(11): 5750-5. (2000).
Shen, X., R.E. Ellis, K. Lee, C.-Y. Liu, K. Yang, A. Solomon, H. Yoshida, R. Morimoto, D.M. Kurnit, K. Mori, and R.J. Kaufman. Complementary Signaling Pathways Regulate the Unfolded Protein Response and Are Required for C. elegans Development. Cell 107: 893-903. (2001).
Silva, M. C., M. D. Amaral, and R.I. Morimoto. Neuronal Reprogramming of Protein Homeostasis by Calcium-Dependent Regulation of the Heat Shock Response. PLoS Genetics 9(8). DOI: 10.1371, e1003711, PMID: 24009518 (2013).
Sinnige, T., G. Meisl, T. C. T. Michaels, M. Vendruscolo, T. P.J. Knowles, and R. I. Morimoto. Kinetic Analysis Reveals that Independent Nucleation Events Determines the Progression of Protein Aggregation in C. elegans. Proc. Natl. Acad. Sci. U.S.A. (in press, 2021).
Solomon A, Bandhakavi S, Jabbar S, Shah R, Beitel GJ, Morimoto RI. Caenorhabditis elegans OSR-1 Regulates Behavioral and Physiological Responses to Hyperosmotic Environments. Genetics 167: 161-170 (2004).
Tatum, M.C., M.D. Chikka, F.K. Oi, L. Chauve, L.A. Martinez-Velazquez, H.W.M. Steinbusch, R.I. Morimoto, and V. Prahlad. Optogenetic Stimulation of Serotonin Release Activates the Heat Shock Response in Distal Tissues of C. elegans. Current Biology 25: 163-174. DOI: 10.1016/j.cub.2014.11.040, PMID: 25557666 (2015).
Van Oosten-Hawle and R. I. Morimoto. Transcellular Chaperone Signaling: An Organismal Strategy for Integrated Cell Stress Responses. Journal of Experimental Biology 217: 129-136. DOI: 10.1242, PMID: 24353212 (2014).
Van Oosten-Hawle, P., and R.I. Morimoto. Organismal Control of Proteostasis by Cell Non-Autonomous Regulation and Transcellular Stress Signaling. Genes and Development 28: 1533-1543. DOI: 10.1101/gad.241125.114, PMID: 25030693 (2014).
Van Oosten-Hawle, P., R. Porter, and R. I. Morimoto. Regulation of Organismal Proteostasis by Transcellular Chaperone Signaling. Cell 153: 1366-1378. DOI:10.1016, PMID: 23746847 (2013).