A5035448367- Cellular transport and secretion
- Autophagy in Disease and Therapy
- Lysosomal Storage Disorders Research
- Endoplasmic Reticulum Stress and Disease
- Wnt/β-catenin signaling in development and cancer
- Advanced Proteomics Techniques and Applications
- Galectins and Cancer Biology
- Toxin Mechanisms and Immunotoxins
- Lipid Membrane Structure and Behavior
- Developmental Biology and Gene Regulation
- Hippo pathway signaling and YAP/TAZ
- Cancer-related gene regulation
- Radiomics and Machine Learning in Medical Imaging
- Amyotrophic Lateral Sclerosis Research
- COVID-19 diagnosis using AI
- Toxoplasma gondii Research Studies
- Cell death mechanisms and regulation
- Alzheimer's disease research and treatments
- Parkinson's Disease Mechanisms and Treatments
- Glycosylation and Glycoproteins Research
- Hedgehog Signaling Pathway Studies
- Mosquito-borne diseases and control
- Machine Learning in Bioinformatics
- Calcium signaling and nucleotide metabolism
- Neurogenetic and Muscular Disorders Research
Harvard University
2015-2025
Boston VA Research Institute
2022-2025
Research Network (United States)
2021-2023
Seoul National University
2022
Casma Therapeutics (United States)
2022
Simon Fraser University
2008-2015
Burnaby Hospital
2012
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of moderate-scale sequencing study aimed at increasing number genes known to contribute predisposition for ALS. performed whole-exome 2869 ALS patients and 6405 controls. Several were found be associated, TBK1 (the gene encoding TANK-binding kinase 1) was identified as an gene. bind phosphorylate proteins involved in innate immunity autophagy, including optineurin...
TBK1 phosphorylates RAB7A-S72 to support multiple downstream steps in PARKIN-dependent mitophagy.
Removal of damaged organelles via the process selective autophagy constitutes a major form cellular quality control. Damaged are recognized by dedicated surveillance machinery, leading to assembly an autophagosome around organelle, prior fusion with degradative lysosomal compartment. Lysosomes themselves also prone damage and degraded through lysophagy. While early steps involve recognition ruptured membranes glycan-binding galectins ubiquitylation transmembrane proteins, many in process,...
Abstract Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. function granulins and why their absence neurodegeneration are unclear. Here we discover that PGRN-deficient human cells murine brains, as well frontal lobes from -mutation FTD patients have increased levels gangliosides, glycosphingolipids contain sialic acid. In these tissues, enzymes catabolize gangliosides were normal, but...
Abstract During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodelling the proteome 1,2 . Although machinery responsible for initiation of has been well characterized 3,4 , our understanding extent to which individual proteins, protein complexes and organelles are selected autophagic degradation, underlying targeting mechanisms, is limited. Here we use orthogonal proteomic strategies provide a spatial...
Abstract Degradation and recycling of plasma membrane proteins occurs via the endolysosomal system, wherein endosomes bud into cytosol from subsequently mature degradative lysosomal compartments. While methods have been developed for rapid selective capture lysosomes (Lyso-IP), analogous isolation early endosome intermediates are lacking. Here, we develop an approach early/sorting through affinity endosome-associated protein EEA1 (Endo-IP) provide proteomic lipidomic snapshots EEA1-positive...
The Wnt/Wingless (Wg) pathway represents a conserved signaling cascade involved in diverse biological processes. Misregulation of Wnt/Wg signal transduction has profound effects on development. Homeodomain-interacting protein kinases (Hipks) represent novel family serine/threonine kinases. Members this group (in particular Hipk2) are implicated as important factors transcriptional regulation to control cell growth, apoptosis and Here, we provide genetic phenotypic evidence that the sole...
Drosophila Homeodomain-interacting protein kinase (Hipk) has been shown to regulate in vivo, the stability of Armadillo, transcriptional effector Wingless signaling. The pathway culminates stabilization Armadillo that, absence signaling, is sequentially phosphorylated, polyubiquitinated and degraded. Loss-of-function clones for hipk result reduced stabilized whereas overexpression elevates levels promote Wingless-responsive target gene expression. Here, we show that can suppress effects...
Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, in endosomal retromer complex are implicated Alzheimer’s Parkinson’s diseases, of Golgi-associated protein (GARP) cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these neurodegeneration is unknown. GARP yeast, including one causing PCCA2, result sphingolipid abnormalities impaired cell growth corrected by treatment...
Lysosomes are subjected to physiological and patho-physiological insults over the course of their life cycle accordingly repaired or recycled. Lysophagy, selective degradation lysosomes via autophagy, occurs upon unrepairable lysosomal membrane rupture; galectins bind glycosylated macromolecules in lysosome lumen, orchestrating a series cellular responses promote autophagic recycling damaged transcriptional upregulation genes. Damaged ubiquitylated, resulting recruitment ubiquitin-binding...
Evolutionarily conserved intercellular signaling pathways regulate embryonic development and adult tissue homeostasis in metazoans. The precise control of the state amplitude is achieved part through kinase- phosphatase-mediated reversible phosphorylation proteins. In this study, we performed a genome-wide vivo RNAi screen for kinases phosphatases that Wnt pathway under physiological conditions Drosophila wing disc. Our analyses have identified 54 high-confidence capable modulating pathway,...
Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between identified autophagy defects, notably accumulation ferritinophagy substrates receptors,...
The Wnt/Wingless (Wg) pathway is an evolutionarily conserved signaling system that used reiteratively, both spatially and temporally, to control the development of multicellular animals. stability cytoplasmic β-catenin/Armadillo, transcriptional effector pathway, controlled by sequential N-terminal phosphorylation ubiquitination targets it for proteasome-mediated degradation. Orthologous members Homeodomain-interacting protein kinase family from Drosophila vertebrates have been implicated in...
ABSTRACT During nutrient stress, macroautophagy is employed to degrade cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome. While machinery responsible for initiation of well characterized, our understanding extent which individual proteins, protein complexes and organelles are selected autophagic degradation, underlying targeting mechanisms limited. Here, we use orthogonal proteomic strategies provide a global molecular...
SUMMARY Lysosomal storage diseases (LSDs) comprised ∼50 monogenic characterized by the accumulation of cellular material in lysosomes and associated defects lysosomal function, but systematic molecular phenotyping is lacking. Here, we develop a nanoflow-based multi-omic single-shot technology (nMOST) workflow allowing simultaneously quantify HeLa cell proteomes lipidomes from more than two dozen LSD mutants, revealing diverse phenotypes. Defects delivery ferritin its autophagic receptor...
The analysis of relative protein abundance has emerged as an important tool in cell biology. Typically, it is possible to quantify >8000 proteins under standard conditions. Tandem Mass Tags (TMT) are isobaric reagents that contain a set isotopically distinct reporter ions, which can be used individual peptides samples through multiplexing(McAlister et al., 2014). Because the TMT performed multiplexed format (up 18 plex), examine effect different perturbations (treatments, time courses,...
The analysis of relative protein abundance has emerged as an important tool in cell biology. Typically, it is possible to quantify >8000 proteins under standard conditions. Tandem Mass Tags (TMT) are isobaric reagents that contain a set isotopically distinct reporter ions, which can be used individual peptides samples through multiplexing(McAlister et al., 2014). Because the TMT performed multiplexed format (up 18 plex), examine effect different perturbations (treatments, time courses,...
SUMMARY Homozygous mutations of granulin precursor ( GRN ) lead to neuronal ceroid lipofuscinosis 1 , a severe neurodevelopmental disease, in humans and neuroinflammation mice 2 . Haploinsufficiency almost invariably causes frontotemporal dementia (FTD) 3,4 The locus produces progranulin (PGRN), lysosomal protein that is cleaved peptides 5,6 Despite intensive investigation, the function granulins reason why their absence neurodegeneration remain unclear. Here, we investigated PGRN lipid...
The analysis of relative protein abundance has emerged as an important tool in cell biology. Typically, it is possible to quantify >8000 proteins under standard conditions. Tandem Mass Tags (TMT) are isobaric reagents that contain a set isotopically distinct reporter ions, which can be used individual peptides samples through multiplexing(McAlister et al., 2014). Because the TMT performed multiplexed format (up 18 plex), examine effect different perturbations (treatments, time courses,...