Abstract
Small VCP Interacting Protein (SVIP) is essential for maintaining a unique form of tubular lysosomes (TLs) in Drosophila . Although Caenorhabditis elegans do not have an annotated SVIP ortholog, expression of Drosophila SVIP in the C. elegans intestine induces TLs constitutively, increases autophagic activity, and extends healthspan. Here, we find that expression of the human ortholog of SVIP in the C. elegans gut causes similar physiological and phenotypic effects as Drosophila SVIP , albeit some effects were less pronounced. These results demonstrate that human SVIP can induce functional TLs in C. elegans but may be a weaker allele compared to Drosophila SVIP .
Figure 1. Human SVIP induces TLs constitutively, increases autophagic activity, and improves healthspan when expressed in the C. elegans gut .
a. Endogenously tagged SPIN-1 ::mCherry in fed adult day 1 WT, dSVIP gut OE, and hSVIP gut OE worms (scale bar, 5μm). b. Quantification of lysosomal junctions/object in fed adult day 1 WT (n=15 worms), dSVIP gut OE (n=15 worms), and hSVIP gut OE (n=14 worms) worms (p-values indicated on graph). c. Gut-expressed SQST-1 ::mCherry::GFP in fed adult day 2 WT, dSVIP gut OE, and hSVIP gut OE worms (scale bar, 100μm). d. GFP/mCherry ratio in fed adult day 2 WT (n=11 worms), dSVIP gut OE (n=13 worms), and hSVIP gut OE (n=15 worms) worms (p-values indicated on graph). e. Gut-expressed Q64::YFP in fed adult day 1 WT, dSVIP gut OE, and hSVIP gut OE (scale bar, 100μm). f. Number of Q64::YFP aggregates in fed adult WT, dSVIP gut OE, and hSVIP gut OE worms on day 1 of adulthood (n=10 for each genotype; p-values indicated on graph). g. Thrashing rate of fed adult WT, dSVIP gut OE, and hSVIP gut OE worms (n=10 worms for each genotype; p-values on graph are comparisons to WT, **p<0.01, ***p<0.001, ****p<0.0001). h. Lifespan of fed adult WT, dSVIP gut OE, and hSVIP gut OE worms. i. Descriptive statistics for the lifespan comparison in Fig. 1h. j. Log-rank test results for lifespan comparisons in Fig. 1h.
Description
Small VCP Interacting Protein (SVIP) was first described as an endogenous inhibitor of Endoplasmic Reticulum-Associated Degradation (Ballar et al., 2007) . Further work showed that SVIP recruits Valosin-Containing Protein (VCP) to lysosomes and is an essential protein for maintaining tubular lysosomal dynamic stability and autophagosomal-lysosomal fusion in Drosophila (Johnson et al., 2021; Johnson et al., 2015; Wang et al., 2011) . Additionally, overexpression of SVIP in Drosophila muscles causes an increase in tubular lysosome (TL) density (Johnson et al., 2021) . Significantly, TL induction correlates with improved animal health, and TL dysfunction has been linked to VCP -dependent diseases, underscoring the potential biomedical relevance of SVIP genes (Villalobos et al., 2023; Wall et al., 2021) .
There is no known SVIP ortholog present in the Caenorhabditis elegans genome; however, our lab previously generated a transgenic C. elegans strain that expresses a codon-optimized Drosophila SVIP gene ( dSVIP ) in the gut (Villalobos et al., 2023) . Although TLs are generally only stimulated in the gut of young-adult C. elegans under conditions of food limitation (Bohnert & Johnson, 2022; Dolese et al., 2022; Ramos et al., 2022) , expression of dSVIP in the gut was sufficient to induce gut TLs constitutively and heighten autophagic activity in young-adult, well-fed C. elegans (Ricaurte-Perez et al., 2024; Villalobos et al., 2023). The human genome encodes an SVIP ortholog ( hSVIP ), which has not been previously characterized in any animal model. In this study, we created a transgenic C. elegans strain that overexpresses a full-length codon-optimized human SVIP transgene in the gut and assessed its effect on TL induction, autophagic activity, lifespan, and healthspan. The purpose of this study was to determine if human SVIP has similar phenotypic and physiological effects as Drosophila SVIP .
To determine if human SVIP overexpression stimulates TL formation constitutively, we overexpressed hSVIP in the gut of a strain expressing the lysosomal membrane protein SPIN-1 endogenously tagged with mCherry. Subsequently, we imaged SPIN-1 ::mCherry in fed day 1 adults, a condition in which TLs are not normally induced (Villalobos et al., 2023) . While TLs were not robustly observed in young well-fed wildtype animals, overexpression of human SVIP induced constitutive TLs to a similar degree as overexpression of Drosophila SVIP ( Figure 1 a-b ). Next, we determined if gut hSVIP overexpression heightened autophagic activity as we observed previously with the Drosophila ortholog (Villalobos et al., 2023) . To do this, we imaged the autophagy receptor, SQST-1 , tandemly tagged with mCherry and GFP ( SQST-1 ::mCherry::GFP) (Villalobos et al., 2023) . This autophagy reporter relies on the principle that GFP fluorescence is sensitive to the acidity in the lysosomal lumen, while mCherry fluorescence is unaffected by the low pH environment (Klionsky et al., 2021) . Hence, low GFP fluorescence is indicative of more autophagic turnover. We imaged SQST-1 ::mCherry::GFP in the intestine of fed day 2 adults overexpressing human or Drosophila SVIP and compared autophagic turnover by quantifying the GFP/mCherry ratio. Overexpression of human SVIP in the gut decreased GFP fluorescence relative to control animals but not to the same extent as gut dSVIP overexpression (Figure 1c-d ). Thus, human SVIP overexpression increases autophagic activity but not as strongly as the Drosophila transgene. Similarly, it has been shown that expression of Drosophila SVIP suppresses protein aggregation, and we were curious if the human transgene would do the same. To do this, we expressed the aggregation-prone protein Q64 (Morley et al., 2002) tagged with yellow fluorescent protein (YFP) in the gut and imaged fed day 1 adults. Indeed, human SVIP reduced protein aggregates in day 1 adults relative to control animals but again not to the same degree as the Drosophila SVIP transgene (Figure 1e-f ). Thus, human SVIP overexpression heightens autophagic activity but not as strongly as Drosophila SVIP .
Next, we explored the physiological effects of human SVIP overexpression in the gut. It has been shown previously that expression of Drosophila SVIP in C. elegans improves healthspan independently of lifespan thereby decreasing the healthspan/lifespan gap (Villalobos et al., 2023) . We found that expression of human SVIP exhibited a comparable improvement in late age mobility, a strong proxy for healthspan (Hahm et al., 2015) , and had only a small effect on lifespan (Figure 1g-i ). Thus, expression of human SVIP promotes healthy aging and increases healthspan similar to expression of the Drosophila SVIP gene.
Collectively, we found that the human SVIP transgene causes similar phenotypic and physiological effects as the Drosophila transgene. Both transgenes induced TLs, heightened autophagic activity, and increased healthspan. Interestingly, while human SVIP did not increase autophagic activity to the same extent as Drosophila SVIP , there was minimal difference in physiological effects between these two strains. Potentially, this could indicate that the maximum autophagic activity triggered by the Drosophila gene is not required to achieve the maximum physiological effects. Future comparative studies on other SVIP orthologs could be informative to designing synthetic SVIP peptides that would maximize the therapeutic potential of SVIP-based strategies aimed at improving healthy aging or combating age-related diseases.
Methods
Animal maintenance
C. elegans were raised at 20ºC on Nematode Growth Medium (NGM) agar (51.3 mM NaCl, 0.25% peptone, 1.7% agar, 1 mM CaCl 2 , 1 mM MgSO 4 , 25 mM KPO 4 , 12.9 µM cholesterol, pH 6.0) that were seeded with E. coli OP50 bacteria. Worms were synchronized by bleaching. Briefly, gravid hermaphrodites were vortexed in 1-2 mL bleaching solution (0.5 M NaOH, 20% bleach) for 3-5 minutes to isolate eggs, and eggs were washed three times in M9 buffer (22 mM KH 2 PO 4 , 42 mM Na 2 HPO 4 , 85.5 mM NaCl, 1 mM MgSO 4 ) before plating on NGM plates seeded with OP50 bacteria. In all aging experiments, including the lifespan assay, adult worms were picked onto fresh OP50-seeded NGM plates every day to separate adults from progeny.
Transgenic strain generation
All strains used in this study were generated using standard genetic crosses or microinjection. For genetic crosses, transgenes expressing fluorescent proteins were tracked by stereomicroscopy. For microinjection, constructs were injected individually or in combination into the gonad of adult hermaphrodites, each at a concentration of 25 ng/µl. Integration of transgenes was achieved using UV irradiation, followed by >5 generations of outcrossing. The dSVIP transgene was generated in a previous study (Villalobos et al., 2023) , and the hSVIP transgene was generated as follows:
P ges-1::hSVIP::unc-54 UTR:
The coding sequence for human SVIP was codon-optimized for C. elegans expression using the C. elegans Codon Adaptor (Redemann et al., 2011) . This sequence, flanked by a 5' attB1 and a 3' attB2 sequence, was then synthesized as a gBlock by Integrated DNA Technologies:
GGGGACAAGTTTGTACAAAAAAGCAGGCTCAAAAaaaaATGGGGTTGTGTTTTCCTTGTCCGGGTGAGTCTGCTCCTCCAACCCCAGATCTTGAGGAGAAGCGGCTAAGCTCGCTGAGGCCGCTGAGCGCCGTCAAAAGGAGGCCGCTTCCCGTGGAATCCTTGACGTCCAATCCGTTCAAGAGAAGCGCAAGAAGAAGGAGAAGATCGAGAAGCAAATCGCCACTTCTGGTCCACCACCAGAGGGAGGACTCCGTTGGACCGTCTCCTAAACCCAGCTTTCTTGTACAAAGTGGTCCCC.
This hSVIP sequence was then cloned into the pDONR221 Gateway entry vector using BP clonase (ThermoFisher), and the insert was verified by DNA sequencing. Ultimately, pDONR221 hSVIP was combined with lab-stock plasmids pDONR P4-P1r P ges-1 and pDONR P2R-P3 unc-54 3' UTR into the pDEST R4-R3 Gateway destination vector using LR clonase (ThermoFisher).
Microscopy methods
For C. elegans whole animal imaging, 4% agarose (Fisher Bioreagents) pads were dried on a Kimwipe (Kimtech) and then placed on top of a Gold Seal TM glass microscope slide (ThermoFisher Scientific). A small volume of 2 mM levamisole (Acros Organics) was spotted on the agarose pad. Worms were transferred to the levamisole spot, and a glass cover slip (Fisher Scientific) was placed on top to complete the mounting. Fluorescence microscopy was performed using a Leica DMi8 THUNDER imager, equipped with 10X (NA 0.32), 40X (NA 1.30), and 100X (NA 1.40) objectives and GFP and Texas Red filter sets.
Image analysis
Images were processed using LAS X software (Leica) and FIJI/ImageJ (NIH). Lysosome networks were analyzed using “Skeleton” analysis plugins in FIJI. Briefly, images were converted to binary 8-bit images and then to skeleton images using the “Skeletonize” plugin. Skeleton images were then quantified using the “Analyze Skeleton” plugin. Number of objects, number of junctions, and object lengths were scored. An “object” is defined by the Analyze Skeleton plugin as a branch connecting two endpoints, an endpoint and junction, or two junctions. Junctions/object was used as a parameter to quantify network integrity. For analyzing fluorescence intensity, the gut tissue was outlined using the free-draw tool in FIJI/ImageJ, and average fluorescence intensity of the outlined area was measured. For SQST-1 ::mCherry::GFP fluorescence ratio experiments, 50% laser intensity, 300 ms exposure time, and 100% Fluorescence Intensity Manager settings were used. For Q64 protein aggregate quantification, fluorescent aggregates were counted manually for each individual worm.
Thrashing and lifespan assays
Synchronous populations of animals were obtained by bleaching gravid adults (see animal maintenance), and worms in the late L4 larval stage were transferred to NGM plates seeded with OP50 bacteria. Throughout both assays, adult worms were transferred to fresh plates every day (to separate adults from their progeny) until reproduction ceased. For thrashing assays, individual worms were transferred into a drop of M9 buffer on an NGM plate, and the number of body bends were counted in a 1-minute period. For lifespans, dead worms were scored every 1-3 days. Worms that exploded, bagged, or crawled off plates were censored during analysis. Lifespans were analyzed using OASIS 2 software (Han et al., 2016) , and statistical significance was assessed using a log-rank test.
Statistical Analyses
Data were statistically analyzed using GraphPad Prism. For all experiments, data distribution was assumed to be normal, but this was not formally tested. For three sample comparisons, a one-way analysis of variance (ANOVA) with Tukey's multiple comparisons was used to determine significance (α = 0.05). For grouped comparisons, a two-way ANOVA with Šídák's multiple comparisons was used to determine significance (α = 0.05). Statistical significance of lifespan data was determined using a log-rank test.
Reagents
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Strain name |
Genotype |
Source |
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Bristol N2 |
Wild type |
Lab stock |
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Villalobos et al., 2023 (by In Vivo Biosystems) |
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louIs5( P ges-1::dSVIP::unc-54 UTR + P odr-1::rfp) III |
Villalobos et al., 2023 |
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louIs5( P ges-1::dSVIP::unc-54 UTR + P odr-1::rfp) III ; spin-1 ( knu1010 [spin-1::mCherry::loxP::HygR::loxP]) V |
Villalobos et al., 2023 |
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louIs7( P ges-1::sqst-1::mCherry::gfp::unc-54 UTR) IV |
Villalobos et al., 2023 |
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louIs5( P ges-1::dSVIP::unc-54 UTR + P odr-1::rfp) III; louIs7( P ges-1::sqst-1::mCherry::gfp::unc-54 UTR) IV |
Villalobos et al., 2023 |
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This study |
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louIs13( P ges-1::hSVIP::unc-54 UTR + P odr-1::rfp) |
This study |
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louIs7( P ges-1::sqst-1::mCherry::gfp::unc-54 UTR) IV; louIs13( P ges-1::hSVIP::unc-54 UTR + Podr-1::rfp) |
This study |
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spin-1 ( knu1010 [spin-1::mCherry::loxP::HygR::loxP]) V; louIs13( P ges-1::hSVIP::unc-54 UTR + P odr-1::rfp) |
This study |
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louIs11( P vha-6::Q64::YFP + rol-6 ( su1006 )); louIs13( P ges-1::hSVIP::unc-54 UTR + P odr-1::rfp) |
This study |
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louIs5( P ges-1::dSVIP::unc-54 UTR + P odr-1::rfp) III; |
This study |
Acknowledgments
Acknowledgments
The authors thank all members of the Bohnert and Johnson labs for helpful discussions on this project.
Funding Statement
Funding for this project comes from the W.M. Keck Foundation (KAB, AEJ) and the National Institutes of Health grants R35GM138116 (AEJ) and R01AG079970 (KAB).
References
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