Hyperactivation of the proteasome in Caenorhabditis elegans protects against proteotoxic stress and extends lifespan

Anderson, Raymond T.; Bradley, Thomas A.; Smith, David M.

doi:10.1016/j.jbc.2022.102415

Cited by 10 publications

(5 citation statements)

References 97 publications

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“…Importantly, we provide in vivo evidence that the diet and clock sensitive subunits of the proteasome in the fat body are important for diet sensitive effects on lifespan, providing a pathway of linking clocks, DR, and aging. Although it is well-established in multiple species that proteasome activity decreases during aging and is generally positively correlated with lifespan (Anderson et al, 2022; Chondrogianni et al, 2015; Huang et al, 2019; Kruegel et al, 2011; Nguyen et al, 2019; Pickering et al, 2015; Tonoki et al, 2009; Vilchez et al, 2012), little is known about its tissue-specific contribution to aging and the link to DR. We found that the knock-down of several cycling proteasome subunits predominantly in the adult fat body, using the S106-GS gal4 (Poirier et al, 2008), significantly reduces lifespan, consistent with whole organism manipulations (Fig. S7).…”

Section: Discussionmentioning

confidence: 99%

“…The proteasome plays a central role in proteostasis by clearing, recycling, and breaking down up to ~ 90% of cellular proteins (Jang, 2018;von Mikecz et al, 2008). In multiple animal models, activation of the proteasome system extends lifespan and healthspan (Anderson et al, 2022;Chondrogianni et al, 2015;Kruegel et al, 2011;Munkacsy et al, 2019;Tonoki et al, 2009;Vilchez et al, 2012). For example, in Drosophila, global overexpression of rpn11, a regulatory subunit of the proteasome complex, extends lifespan while knock-down of rpn11 decreases lifespan (Tonoki et al, 2009).…”

Section: Knockdown Of Proteasome Subunit Genes In Fat Body Limited No...mentioning

confidence: 99%

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Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Hwangbo

Kwon

Iwanaszko

et al. 2023

Preprint

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Circadian clocks may mediate lifespan extension by caloric or dietary restriction (DR). We find that the core clock transcription factor Clock is crucial for a robust longevity and fecundity response to DR in Drosophila. To identify clock-controlled mediators, we performed RNA-sequencing from abdominal fat bodies across the 24 h day after just 5 days under control or DR diets. In contrast to more chronic DR regimens, we did not detect significant changes in the rhythmic expression of core clock genes. Yet we discovered that DR induced de novo rhythmicity or increased expression of rhythmic clock output genes. Network analysis revealed that DR increased network connectivity in one module comprised of genes encoding proteasome subunits. Adult, fat body specific RNAi knockdown demonstrated that proteasome subunits contribute to DR-mediated lifespan extension. Thus, clock control of output links DR-mediated changes in rhythmic transcription to lifespan extension.

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Section: Discussionmentioning

confidence: 99%

Section: Knockdown Of Proteasome Subunit Genes In Fat Body Limited No...mentioning

confidence: 99%

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Hwangbo

Kwon

Iwanaszko

et al. 2023

Preprint

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“…The function of the UPS is critical for the healthy maintenance of the proteome in general, and more specifically, for neuronal synapse function (i.e., plasticity and synaptic protein turnover) 1,35 . Based on our prior findings of oligomer impairment 20 , we generated the first multicellular organism (C. elegans) with a constitutively open 20S proteasome, that could not be inhibited by these toxic oligomers 36 . These worms with "hyperactive" 20S proteasomes have increased longevity and resistance to various proteotoxicities, including heat shock and oxidative damage.…”

Section: Discussionmentioning

confidence: 99%

“…These worms with "hyperactive" 20S proteasomes have increased longevity and resistance to various proteotoxicities, including heat shock and oxidative damage. Moreover, increasing proteasome amount or activity in mammalian cell culture and multicellular organisms by various means has also proven feasible, and to increase degradation of endogenous and ND related proteins [36][37][38][39][40][41] .…”

Section: Discussionmentioning

confidence: 99%

Minimal mechanistic component of HbYX-dependent proteasome activation

Smith

Thibaudeau

Rexroad

2023

Preprint

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The implication of reduced proteasomal function in neurodegenerative diseases combined with numerous studies showing the protective effects of increasing proteasome activity in animal models justify the need to understand how the proteasome is activated for protein degradation. The C-terminal HbYX motif is present on many proteasome binding proteins and functions to tether activators to the 20S core particle. Peptides with a HbYX motif can also autonomously activate 20S gate-opening to allow protein degradation, but the underlying allosteric molecular mechanism is not clear. We designed a HbYX-like dipeptide mimetic that represents only the fundamental components of the HbYX motif to allow rigorous elucidation of the underlying molecular mechanisms of HbYX induced 20S gate-opening in the archaeal and mamalian proteasome. By generating several high-resolution cryo-EM structures (e.g. 1.9Å) we identified multiple proteasome α subunit residues involved in HbYX-dependent activation and the conformational changes involved in gate-opening. In addition, we generated mutants probing these structural findings and identified specific point mutations that strongly activate the proteasome by partially mimicking a HbYX-bound state. These structures resolve 3 novel mechanistic features that are critical for allosteric α subunit conformational changes that ultimately trigger gate-opening: 1) rearrangement of the loop adjacent to K66, 2) inter- and intra- α subunit conformational changes and 3) a pair of IT residues on the α N-terminus in the 20S channel that alternate binding sites to stabilize the open and closed states. All gate-opening mechanisms appear to converge on this “IT switch”. When stimulated by the mimetic, the human 20S can degrade unfolded proteins such as tau, and prevent proteasomal inhibition by toxic soluble oligomers. Collectively, the results presented here provide a mechanistic model of HbYX-dependent 20S gate-opening and offer proof of concept for the robust potential of HbYX-like small molecules to stimulate proteasome function, which could be useful to treat neurodegenerative diseases.

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“…The core 20S particle of a proteasome contains proteolytic sites, which become accessible after association with the 19S cap, facilitating the degradation of polyubiquitinated proteins or 11S and PA200 regulators, allowing the degradation of polypeptides and unstructured proteins not modified with ubiquitin (5)(6)(7)(8)(9)). An increasing number of studies have demonstrated that stimulation of proteasomes increases cell resistance to various types of proteotoxic stressors and delays aging (10)(11)(12)(13)(14)(15)(16). Some of the investigated approaches to stimulating proteasomes include overexpression of individual proteasome subunits (e.g., PSMD11, β5, 11Sα, and α3ΔΝ), modulation of proteasome activity through phosphorylation, and the development of small compounds and peptides capable of opening 20S particles to allow access to their proteolytic sites by certain protein substrates (4,(15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness

et al. 2023

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Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosphorylation, or conformational changes induced by small molecules or peptides. In contrast to these approaches, we evaluated a transcription-driven increase in the total proteasome pool to enhance the proteolytic capacity of degenerating retinal neurons. We show that overexpression of nuclear factor erythroid-2-like 1 (Nfe2l1) transcription factor stimulated proteasome biogenesis and activity, improved the clearance of the ubiquitin-proteasomal reporter, and delayed photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins. The findings highlight Nfe2l1 as an emerging therapeutic target to treat neurodegenerative diseases linked to protein misfolding.

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Hyperactivation of the proteasome in Caenorhabditis elegans protects against proteotoxic stress and extends lifespan

Cited by 10 publications

References 97 publications

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Minimal mechanistic component of HbYX-dependent proteasome activation

Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness

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