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

AbstractDuring 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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Tissue-specific regulation of epidermal contraction during C. elegans embryonic morphogenesis

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkab164 ◽

2021 ◽

Author(s):

Elizabeth D Drewnik ◽

Tobias Wiesenfahrt ◽

Ryan B Smit ◽

Ye-Jean Park ◽

Linda M Pallotto ◽

...

Keyword(s):

Rho Kinase ◽

The Other ◽

Cell Type ◽

Tissue Specific ◽

C Elegans ◽

Lateral Contraction ◽

Embryonic Morphogenesis ◽

Specific Regulation ◽

Primary Focus ◽

P21 Activated Kinase

Abstract Actin and myosin mediate the epidermal cell contractions that elongate the Caenorhabditis elegans embryo from an ovoid to a tubular-shaped worm. Contraction occurs mainly in the lateral epidermal cells, while the dorsoventral epidermis plays a more passive role. Two parallel pathways trigger actinomyosin contraction, one mediated by LET-502/Rho kinase and the other by PAK-1/p21 activated kinase. A number of genes mediating morphogenesis have been shown to be sufficient when expressed either laterally or dorsoventrally. Additional genes show either lateral or dorsoventral phenotypes. This led us to a model where contractile genes have discrete functions in one or the other cell type. We tested this by examining several genes for either lateral or dorsoventral sufficiency. LET-502 expression in the lateral cells was sufficient to drive elongation. MEL-11/Myosin phosphatase, which antagonizes contraction, and PAK-1 were expected to function dorsoventrally, but we could not detect tissue-specific sufficiency. Double mutants of lethal alleles predicted to decrease lateral contraction with those thought to increase dorsoventral force were previously shown to be viable. We hypothesized that these mutant combinations shifted the contractile force from the lateral to the dorsoventral cells and so the embryos would elongate with less lateral cell contraction. This was tested by examining ten single and double mutant strains. In most cases, elongation proceeded without a noticeable alteration in lateral contraction. We suggest that many embryonic elongation genes likely act in both lateral and dorsoventral cells, even though they may have their primary focus in one or the other cell type.

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Organism-wide single-cell transcriptomics of long-lived C. elegans daf-2-/- mutants reveals tissue-specific reprogramming of gene expression networks

10.1101/509992 ◽

2019 ◽

Author(s):

Jessica L. Preston ◽

Nicholas Stiffler ◽

Maggie Weitzman

Keyword(s):

Gene Expression ◽

Single Cell ◽

Expression Profiles ◽

Regulation Of Gene Expression ◽

Gene Expression Profiles ◽

Machine Learning Algorithms ◽

Wild Type ◽

Tissue Specific ◽

C Elegans ◽

Specific Regulation

AbstractA critical requirement for a systems-level understanding of complex biological processes such as aging is the ability to directly characterize interactions between cells and tissues within a multicellular organism. C. elegans nematodes harboring mutations in the insulin-like receptor daf-2 exhibit dramatically-increased lifespans. To identify tissue-specific biochemical mechanisms regulating aging plasticity, we single-cell sequenced 3’-mRNA libraries generated from seven populations of whole day-one adult wild-type and daf-2-/- worms using the 10x ChromiumV1™platform. The age-synchronized samples were bioinformatically merged into a single aligned dataset containing 40,000 age-synchronized wild-type and daf-2-/- cellular transcriptomes partitioned into 101 clusters, using unsupervised machine-learning algorithms to identify common cell types. Here we describe the basic features of the adult C. elegans single-cell transcriptome and summarize functional alterations observed in the gene expression profiles of long-lived daf-2-/- worms. Comprehensive methods and datasets are provided. This is the first study to directly quantify cell-specific differential gene expression between two age-synchronized, genetically-distinct populations of multicellular organisms. This novel approach answers fundamental questions regarding tissue-specific regulation of gene expression and helps to establish a foundation for a comprehensive C. elegans single-cell gene expression atlas.

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A cullin-RING ubiquitin ligase promotes thermotolerance as part of the Intracellular Pathogen Response in C. elegans

10.1101/586834 ◽

2019 ◽

Cited By ~ 4

Author(s):

Johan Panek ◽

Spencer S. Gang ◽

Kirthi C. Reddy ◽

Robert J. Luallen ◽

Amitkumar Fulzele ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Protein Quality ◽

Transcriptional Response ◽

Intracellular Pathogen ◽

Protein Homeostasis ◽

Pathogen Infection ◽

C Elegans ◽

Proteotoxic Stress ◽

Expression Of Genes ◽

Pathogen Response

AbstractIntracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematode C. elegans called 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 cullin cul-6, which promotes thermotolerance in pals-22 mutants. However, it was unclear whether CUL-6 acted alone, or together with other ubiquitin ligase components. Here we use co-immunoprecipitation 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 co-immunoprecipitate with CUL-6 and find that FBXA-158 promotes thermotolerance. In summary, we have defined the three core components and an F-box adaptor of a cullin-RING ligase complex that promotes thermotolerance as part of the IPR in C. elegans, which adds to our understanding of how organisms cope with proteotoxic stress.Significance StatementIntracellular pathogen infection in the nematode Caenorhabditis elegans induces a robust transcriptional response as the host copes with infection. This response program includes several ubiquitin ligase components that are predicted to function in protein quality control. In this study, we show that these infection-induced ubiquitin ligase components form a protein complex that promotes increased tolerance of acute heat stress, an indicator of improved protein homeostasis capacity. These findings show that maintaining protein homeostasis may be a critical component of a multifaceted approach allowing the host to deal with stress caused by intracellular infection.

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Tissue-specific regulation of 1,25-dihydroxyvitamin D action in the target tissues of rats

10.31274/rtd-180813-11797 ◽

1993 ◽

Author(s):

Matthew John Beckman

Keyword(s):

Tissue Specific ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Specific Regulation

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Faculty Opinions recommendation of Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1009702.182184 ◽

2003 ◽

Author(s):

Mark Fortini

Keyword(s):

Genetic Factors ◽

Tissue Specific ◽

C Elegans

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Faculty Opinions recommendation of Systematic analysis of tissue-restricted miRISCs reveals a broad role for microRNAs in suppressing basal activity of the C. elegans pathogen response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14267090.15779223 ◽

2012 ◽

Author(s):

Jean-Luc Imler

Keyword(s):

Systematic Analysis ◽

C Elegans ◽

Basal Activity ◽

Pathogen Response ◽

Broad Role

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Faculty Opinions recommendation of Widespread protein aggregation as an inherent part of aging in C. elegans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4877956.14304055 ◽

2011 ◽

Author(s):

Anne Brunet ◽

Jana Lim

Keyword(s):

Protein Aggregation ◽

C Elegans ◽

Inherent Part

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Caenorhabditis elegans Junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

Genetics ◽

10.1093/genetics/iyab063 ◽

2021 ◽

Author(s):

Christopher A Piggott ◽

Zilu Wu ◽

Stephen Nurrish ◽

Suhong Xu ◽

Joshua M Kaplan ◽

...

Keyword(s):

Calcium Channels ◽

Calcium Channel ◽

Tissue Specific ◽

Voltage Gated ◽

Membrane Contact Sites ◽

Contact Sites ◽

Pharyngeal Muscles ◽

Membrane Contact ◽

Null Mutants

Abstract The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Nature Communications ◽

10.1038/s41467-020-20269-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

José M. Monje-Moreno ◽

Ana María Brokate-Llanos ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Caenorhabditis Elegans ◽

Protein Aggregation ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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