Extracellular proteostasis prevents aggregation during pathogenic attack

Gallotta, Ivan; Sandhu, Aneet Pal Singh; Peters, Maximilian; Haslbeck, Martin; Jung, Raimund; Agilkaya, Sinem; Blersch, Jane L.; Rödelsperger, Christian; Röseler, Waltraud; Huang, Chaolie; Sommer, Ralf J.; David, Della

doi:10.1038/s41586-020-2461-z

Cited by 45 publications

(55 citation statements)

References 43 publications

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“…We observed tissue-specific gene ontology (GO) enrichment of the best longevity correlated genes (Figure 3 and Supplementary Table 3). These include several processes known to be vital to promote healthy aging, such as immune responses, neuronal signaling, heat shock proteins, epigenetic reprogramming, extracellular matrix, and mitochondrial energy metabolism (Figure 3; Greer et al, 2011;Houtkooper et al, 2013;López-Otín et al, 2013;Ewald et al, 2015;Denzel et al, 2019;Ewald, 2019;Hess et al, 2019;Vertti-Quintero et al, 2019;Gallotta et al, 2020). For instance, the adrenal gland showed enrichment for immune responses, whereas in the liver, oxidative phosphorylation and mitochondrial components were enriched (Figure 3).…”

Section: Gene Expression Correlating With Lifespanmentioning

confidence: 99%

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

et al. 2021

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Although genetic approaches have identified key genes and pathways that promote longevity, systems-level approaches are less utilized. Here, we took advantage of the wealth of omics data characterizing the BXD family of mice. We associated transcript and peptide levels across five tissues from both female and male BXD isogenic lines with their median lifespan. We identified over 5000 genes that showed a longevity correlation in a given tissue. Surprisingly, we found less than 1% overlap among longevity-correlating genes across tissues and sex. These 1% shared genes consist of 51 genes, of which 13 have been shown to alter lifespan. Only two genes -Coro7 and Set- showed a longevity correlation in all tissues and in both sexes. While differential regulation of aging across tissues and sex has been reported, our systems-level analysis reveals two unique genes that may promote healthy aging in unique sex- and tissue-agnostic manner.

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Section: Gene Expression Correlating With Lifespanmentioning

confidence: 99%

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

et al. 2021

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“…Upon infection, the host triggers the IPR transcriptional program, which is distinct from the response to extracellular pathogens [46, 62, 63]. One of the host’s defense strategies against intracellular and extracellular pathogens is to improve resilience by enhancing proteostasis [2, 46, 62, 64]. Our work reveals that upon failure of PQC the organism co-opts part of the response to intracellular pathogens by inducing IPR genes such as pals-5 to protect the pharynx against excessive proteostress.…”

Section: Discussionmentioning

confidence: 99%

“…Active mechanisms to ensure functional and undamaged proteins are crucial across lifeforms [1]. A healthy proteome is maintained both inside and outside cells by a complex network of proteostasis components [2, 3]. However, with age, disruption of protein folding and proteolytic activities leads to a decline in proteostasis capacity [3].…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging

Jung

Lechler

Rödelsperger

et al. 2020

Preprint

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During aging, proteostasis capacity declines and aggregation-prone proteins become instable, accumulating in protein aggregates both inside and outside cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of three core protein quality control systems, i.e. chaperones, proteasome and macroautophagy, leads to lower levels of age-dependent protein aggregation in C. elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism called SAPA that selectively targets newly synthesized aggregation-prone proteins to suppress aggregation and proteotoxicity. vha-12 and scav-3 mutants reveal that SAPA relies on macroautophagy-independent lysosomal degradation. Furthermore, SAPA involves several previously uncharacterized components of the intracellular pathogen response. We propose that SAPA represents an anti-aggregation machinery targeting aggregation-prone proteins for lysosomal degradation.

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“…This observation echoes the effect of apolipoprotein E in Alzheimer's disease widely reported in literature and may deserve further biochemical analysis. [85][86][87][88] Oligomeric proteins that involve subunit exchange between wild-type and mutant proteins in a heterozygous mixture pose further technical challenge to study the co-aggregation process and the interplay in the thermodynamic stability. In particular, patients carrying pathogenic TTR mutations are oen heterozygous.…”

Section: The Complexity Of Protein Co-aggregation In Transthyretin Amyloidosismentioning

confidence: 99%

Quantitative interrogation of protein co-aggregation using multi-color fluorogenic protein aggregation sensors

et al. 2021

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Extracellular proteostasis prevents aggregation during pathogenic attack

Cited by 45 publications

References 43 publications

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity

Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging

Quantitative interrogation of protein co-aggregation using multi-color fluorogenic protein aggregation sensors

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