Expanding the Organismal Proteostasis Network: Linking Systemic Stress Signaling with the Innate Immune Response

Miles, Jay; Scherz-Shouval, Ruth; Oosten-Hawle, Patricija van

doi:10.1016/j.tibs.2019.06.009

Cited by 41 publications

(33 citation statements)

References 147 publications

(207 reference statements)

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“…Moreover, evidence is accumulating that proteins involved in the immune response can also act as signaling factors in the proteostasis network. Ultimately, therefore, immune and stress‐response pathways can thus be probed by small molecules that allosterically act on Hsps and influence the PPI networks of which Hsps are hubs …”

Section: Introductionmentioning

confidence: 99%

“…Ultimately, therefore, immune and stress-response pathways can thus be probedb ys mall molecules that allosterically act on Hsps and influence the PPI networks of which Hsps are hubs. [8] The crucial challenge in the designo fallosteric ligands effectively consists in identifying chemical entitiest hat are truly capable of selectively interfering with ap rotein's key functional conformational substrates, with these substrates' interactions with other proteins, and with fundamentale ventso ccurring furtherd ownstream in cell-signaling pathways. Meeting this challenge will enable the use of specific molecules to target distinct,c ircumscribed aspects of the molecular mechanisms that control cell biology,n ot only identifying salient traits of how signaling pathways are modulated (and consequently en-hancing our knowledge of complex biological systems) but also, ultimately,l eading to this knowledge being invested in the discovery of pathway regulators with uniquet herapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

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Designing Molecular Spanners to Throw in the Protein Networks

Serapian

Colombo

2020

Chemistry A European J

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Proteins govern most aspects of cellular life and, through specific interfaces, are typically involved in intricate protein–protein interaction (PPI) networks and signaling pathways. Subtle up‐ or downregulation of key protein functions and PPIs results in disease; still, the preferred option to contrast the role of a protein in disease and healthy conditions alike remains its outright shutdown through orthosteric ligands that block its active site. Here, we explore subtler alternatives to modulate proteins and PPIs. Driven by a view of proteins as dynamic entities, we discuss ways to identify allosteric binding sites, which, when targeted by tailored ligands, can induce significant changes in the active site of a protein, and lead to agonistic or antagonistic effects. We also summarize the selective regulation of specific PPIs—either direct or allosteric—and show that effects can be stabilizing as well as destabilizing, depending on how the conformational equilibrium of a protein is shifted.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Designing Molecular Spanners to Throw in the Protein Networks

Serapian

Colombo

2020

Chemistry A European J

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“…Pathogen infection can perturb proteostasis and several studies in the nematode Caenorhabditis elegans have demonstrated intriguing connections between immune responses to extracellular pathogens and canonical proteostasis pathways (6)(7)(8)(9)(10)(11). More recently, examining the C. elegans host response to intracellular pathogens has uncovered a novel stress response pathway that promotes proteostasis (12,13).…”

mentioning

confidence: 99%

A cullin-RING ubiquitin ligase promotes thermotolerance as part of the intracellular pathogen response in Caenorhabditis elegans

Panek

Gang

Reddy

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Intracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematodeCaenorhabditis eleganscalled the intracellular pathogen response (IPR), which promotes resistance to proteotoxic stress and appears to be distinct from canonical proteostasis pathways. The IPR is controlled by PALS-22 and PALS-25, proteins of unknown biochemical function, which regulate expression of genes induced by natural intracellular pathogens. We previously showed that PALS-22 and PALS-25 regulate the mRNA expression of the predicted ubiquitin ligase component cullincul-6, which promotes thermotolerance inpals-22mutants. However, it was unclear whether CUL-6 acted alone, or together with other cullin-ring ubiquitin ligase components, which comprise a greatly expanded gene family inC. elegans. Here we use coimmunoprecipitation studies paired with genetic analysis to define the cullin-RING ligase components that act together with CUL-6 to promote thermotolerance. First, we identify a previously uncharacterized RING domain protein in the TRIM family we named RCS-1, which acts as a core component with CUL-6 to promote thermotolerance. Next, we show that the Skp-related proteins SKR-3, SKR-4, and SKR-5 act redundantly to promote thermotolerance with CUL-6. Finally, we screened F-box proteins that coimmunoprecipitate with CUL-6 and find that FBXA-158 and FBXA-75 promote thermotolerance. In summary, we have defined the three core components and two F-box adaptors of a cullin-RING ligase complex that promotes thermotolerance as part of the IPR inC. elegans, which adds to our understanding of how organisms cope with proteotoxic stress.

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“…The cellular stress response is a major regulator of the proteostasis network in various scenarios of induced imbalance in proteostasis. A growing body of evidence indicates that immune reactions are induced by proteostatic stress, and excessive inflammation may contribute to dysfunctional proteostasis [ 76 ]. Here, we review the interplay between the immune response and proteostasis, particularly in the context of neurodegenerative diseases.…”

Section: Immune Responses Induced By Dysfunctional Proteostasis Inmentioning

confidence: 99%

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Sonninen

Goldsteins

Laham-Karam

et al. 2020

Cells

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Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

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Expanding the Organismal Proteostasis Network: Linking Systemic Stress Signaling with the Innate Immune Response

Cited by 41 publications

References 147 publications

Designing Molecular Spanners to Throw in the Protein Networks

Designing Molecular Spanners to Throw in the Protein Networks

A cullin-RING ubiquitin ligase promotes thermotolerance as part of the intracellular pathogen response in Caenorhabditis elegans

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

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