Vincenzo Sorrentino
Email Address
vsorrent@nus.edu.sg
Organizational Units
YONG LOO LIN SCH OF MEDICINE
faculty
BIOCHEMISTRY
dept
35 results
Publication Search Results
Now showing 1 - 10 of 35
Publication The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL(LIPPINCOTT WILLIAMS & WILKINS, 2016-02-05) Nelson, Jessica Kristine; Sorrentino, Vincenzo; Trezza, Rossella Avagliano; Heride, Claire; Urbe, Sylvie; Distel, Ben; Zelcer, Noam; Dr Vincenzo Sorrentino; BIOCHEMISTRYRationale: The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDLcholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. Objective: To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. Methods and Results: Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. Conclusions: Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.Publication Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia(Springer Science and Business Media LLC, 2024-01-26) Membrez, Mathieu; Migliavacca, Eugenia; Christen, Stefan; Yaku, Keisuke; Trieu, Jennifer; Lee, Alaina K; Morandini, Francesco; Giner, Maria Pilar; Stiner, Jade; Makarov, Mikhail V; Garratt, Emma S; Vasiloglou, Maria F; Chanvillard, Lucie; Dalbram, Emilie; Ehrlich, Amy M; Sanchez-Garcia, José Luis; Canto, Carles; Karagounis, Leonidas G; Treebak, Jonas T; Migaud, Marie E; Heshmat, Ramin; Razi, Farideh; Karnani, Neerja; Ostovar, Afshin; Farzadfar, Farshad; Tay, Stacey KH; Sanders, Matthew J; Lillycrop, Karen A; Godfrey, Keith M; Nakagawa, Takashi; Moco, Sofia; Koopman, René; Lynch, Gordon S; Sorrentino, Vincenzo; Feige, Jerome N; Dr Vincenzo Sorrentino; BIOCHEMISTRYAbstractMitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1–3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss–Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.Publication Cytosolic Proteostasis Networks of the Nlitochondrial Stress Response(ELSEVIER SCIENCE LONDON, 2017-09) D'Amico, Davide; Sorrentino, Vincenzo; Auwerx, Johan; Dr Vincenzo Sorrentino; BIOCHEMISTRYMitochondrial stress requires timely intervention to prevent mitochondrial and cellular dysfunction. Re-establishing the correct protein homeostasis is crucial for coping with mitochondrial stress and maintaining cellular homeostasis. The best-characterized adaptive pathways for mitochondrial stress involve a signal originating from stressed mitochondria that triggers a nuclear response. However, recent findings have shown that mitochondrial stress also affects a complex network of protein homeostasis pathways in the cytosol. We review how mitochondrial dysregulation affects cytosolic proteostasis by regulating the quantity and quality of protein synthesis, protein stability, and protein degradation, leading to an integrated regulation of cellular metabolism and proliferation. This mitochondria to cytosol network extends the current model of the mitochondrial stress response, with potential applications in the treatment of mitochondrial disease. Cytosolic proteostatic networks activated during mitochondrial stress involve the regulation of protein synthesis, folding, and degradation, and act in parallel to nucleus-dependent mechanisms. Cap-dependent protein synthesis is inhibited upon mitochondrial stress, while cap-independent translation mechanisms are activated to synthesize stress-associated proteins. The activity of the proteasome is induced during stress by the accumulation of mitochondrial precursors, but is inhibited by electron transport chain dysfunction leading to oxidative stress. Reduced mtHSP70 expression or alteration of lipid metabolism can simultaneously activate the mitochondrial unfolded protein response and the heat shock response to restore mitochondrial and cytosolic proteostasis. Positive regulators of protein synthesis are induced in mitochondrial diseases, and inhibiting translation ameliorates the pathological phenotype by reducing energy consumption and proteotoxicity.Publication The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging(CELL PRESS, 2019-02-21) D'Amico, Davide; Mottis, Adrienne; Potenza, Francesca; Sorrentino, Vincenzo; Li, Hao; Romani, Mario; Lemos, Vera; Schoonjans, Kristina; Zamboni, Nicola; Knott, Graham; Schneider, Bernard L; Auwerx, Johan; Dr Vincenzo Sorrentino; BIOCHEMISTRYLittle information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (Mff), thereby impairing mitochondrial fission and mitophagy. This mechanism is conserved in C. elegans by the PUM2 ortholog PUF-8. puf-8 knock-down in old nematodes and Pum2 CRISPR/Cas9-mediated knockout in the muscles of elderly mice enhances mitochondrial fission and mitophagy in both models, hence improving mitochondrial quality control and tissue homeostasis. Our data reveal how a PUM2-mediated layer of post-transcriptional regulation links altered Mff translation to mitochondrial dynamics and mitophagy, thereby mediating age-related mitochondrial dysfunctions. Aging leads to alterations in several key biological processes. However, whether and how these age-associated dysfunctions are interconnected is still poorly understood. Here, D'Amico et al. discovered that the RNA-binding protein PUM2 is induced upon aging and links impaired protein homeostasis and mitochondrial dysfunction, two well-known hallmarks of aging.Publication Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia(SPRINGER BASEL AG, 2021-11) Luciani, Alessandro; Denley, Matthew CS; Govers, Larissa P; Sorrentino, Vincenzo; Froese, D Sean; Dr Vincenzo Sorrentino; BIOCHEMISTRYMitochondria—the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat—are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding—and potentially reversing—the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health.Publication The movement tracker: A flexible system for automated movement analysis in invertebrate model organisms(Wiley, 2016-10) Mouchiroud, L; Sorrentino, V; Williams, EG; Cornaglia, M; Frochaux, MV; Lin, T; Nicolet-dit-Félix, AA; Krishnamani, G; Ouhmad, T; Gijs, MAM; Deplancke, B; Auwerx, J; Dr Vincenzo Sorrentino; BIOCHEMISTRYPhenotyping strategies in simple model organisms such as D. melanogaster and C. elegans are often broadly limited to growth, aging, and fitness. Recently, a number of physical setups and video tracking software suites have been developed to allow for accurate, quantitative, and high-throughput analysis of movement in flies and worms. However, many of these systems require precise experimental setups and/or fixed recording formats.We report here an update to the Parallel Worm Tracker software, which we termed the Movement Tracker. The Movement Tracker allows variable experimental setups to provide crossplatform automated processing of a variety of movement characteristics in both worms and flies and permits the use of simple physical setups that can be readily implemented in any laboratory. This software allows high-throughput processing capabilities and high levels of flexibility in video analysis, providing quantitative movement data on C. elegans and D. melanogaster in a variety of different conditions.Publication Track C. Biomedical Instrumentation & Micro and Nano Systems.(Walter de Gruyter GmbH, 2016-09-28) Cornaglia, Matteo; Mouchiroud, Laurent; Krishnamani, Gopalan; Marette, Alexis; Narasimhan, Shreya; Jovaisaite, Virginija; Sorrentino, Vincenzo; Lehnert, Thomas; Auwerx, Johan; Gijs, Martin AM; Dr Vincenzo Sorrentino; BIOCHEMISTRYPublication LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P(OXFORD UNIV PRESS, 2017-06-01) Hakonen, Johanna E; Sorrentino, Vincenzo; Trezza, Rossella Avagliano; de Wissel, Marit B; van den Berg, Marlene; Bleijlevens, Boris; van Ruissen, Fred; Distel, Ben; Baas, Frank; Zelcer, Noam; Weterman, Marian AJ; Dr Vincenzo Sorrentino; BIOCHEMISTRYCharcot-Marie-Tooth (CMT) disease type 2 is a genetically heterogeneous group of inherited neuropathies characterized by motor and sensory deficits as a result of peripheral axonal degeneration. We recently reported a frameshift (FS) mutation in the Really Interesting New Gene finger (RING) domain of LRSAM1 (c.2121_2122dup, p. Leu708Argfs) that encodes an E3 ubiquitin ligase, as the cause of axonal-type CMT (CMT2P). However, the frequency of LRSAM1 mutations in CMT2 and the functional basis for their association with disease remains unknown. In this study, we evaluated LRSAM1 mutations in two large Dutch cohorts. In the first cohort (n=107), we sequenced the full LRSAM1 coding exons in an unbiased fashion, and, in the second cohort (n=468), we specifically sequenced the last, RING-encoding exon in individuals where other CMTassociated genes had been ruled out. We identified a novel LRSAM1 missense mutation (c.2120C > T, p. Pro707Leu) mapping to the RING domain. Based on our genetic analysis, the occurrence of pathogenic LRSAM1 mutations is estimated to be rare. Functional characterization of the FS, the identified missense mutation, as well as of another recently reported pathogenic missense mutation (c.2081G > A, p. Cys694Tyr), revealed that in vitro ubiquitylation activity was largely abrogated. We demonstrate that loss of the E2-E3 interaction that is an essential prerequisite for supporting ubiquitylation of target substrates, underlies this reduced ubiquitylation capacity. In contrast, LRSAM1 dimerization and interaction with the bona fide target TSG101 were not disrupted. In conclusion, our study provides further support for the role of LRSAM1 in CMT and identifies LRSAM1-mediated ubiquitylation as a common determinant of disease-associated LRSAM1 mutations.Publication The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-06-25) Hong, Cynthia; Duit, Sarah; Jalonen, Pilvi; Out, Ruud; Scheer, Lilith; Sorrentino, Vincenzo; Boyadjian, Rima; Rodenburg, Kees W; Foley, Edan; Korhonen, Laura; Lindholm, Dan; Nimpf, Johannes; van Berkel, Theo JC; Tontonoz, Peter; Zelcer, Noam; Dr Vincenzo Sorrentino; BIOCHEMISTRYWe have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results indecreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.Publication Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein(OXFORD UNIV PRESS, 2013-05) Sorrentino, Vincenzo; Fouchier, Sigrid W; Motazacker, Mohammad M; Nelson, Jessica K; Defesche, Joep C; Dallinga-Thie, Geesje M; Kastelein, John JP; Hovingh, G Kees; Zelcer, Noam; Dr Vincenzo Sorrentino; BIOCHEMISTRYAimsRecent genome-wide association studies suggest that IDOL (also known as MYLIP) contributes to variation in circulating levels of low-density lipoprotein cholesterol (LDL-C). IDOL, an E3-ubiquitin ligase, is a recently identified post-transcriptional regulator of LDLR abundance. Briefly, IDOL promotes degradation of the LDLR thereby limiting LDL uptake. Yet the exact role of IDOL in human lipoprotein metabolism is unclear. Therefore, this study aimed at identifying and functionally characterizing IDOL variants in the Dutch population and to assess their contribution to circulating levels of LDL-C.Methods and resultsWe sequenced the IDOL coding region in 677 individuals with LDL-C above the 95th percentile adjusted for age and gender (high-LDL-C cohort) in which no mutations in the LDLR, APOB, and PCSK9 could be identified. In addition, IDOL was sequenced in 560 individuals with baseline LDL-C levels below the 20th percentile adjusted for age and gender (low-LDL-C cohort). We identified a total of 14 IDOL variants (5 synonymous, 8 non-synonymous, and 1 non-sense). Functional characterization of these variants demonstrated that the p.Arg266X variant represents a complete loss of IDOL function unable to promote ubiquitylation and subsequent degradation of the LDLR. Consistent with loss of IDOL function, this variant was identified in individuals with low circulating LDL-C.ConclusionOur results support the notion that IDOL contributes to variation in circulating levels of LDL-C. Strategies to inhibit IDOL activity may therefore provide a novel therapeutic venue to treating dyslipidaemia. © 2013 The Author.