A5001971427- Autophagy in Disease and Therapy
- Cellular transport and secretion
- Calcium signaling and nucleotide metabolism
- Mitochondrial Function and Pathology
- Lysosomal Storage Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Ubiquitin and proteasome pathways
- Retinal Diseases and Treatments
- Retinal Development and Disorders
- Adenosine and Purinergic Signaling
- Protein Degradation and Inhibitors
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Endoplasmic Reticulum Stress and Disease
- Plant responses to water stress
- Autoimmune and Inflammatory Disorders Research
- Protein Kinase Regulation and GTPase Signaling
- Sirtuins and Resveratrol in Medicine
- CRISPR and Genetic Engineering
- Genomics, phytochemicals, and oxidative stress
- Organ Transplantation Techniques and Outcomes
- Cancer, Hypoxia, and Metabolism
- Cardiac Ischemia and Reperfusion
- Lipid Membrane Structure and Behavior
- Pancreatic function and diabetes
University of Dundee
2016-2025
MRC Protein Phosphorylation and Ubiquitylation Unit
2015-2024
Medical Research Council
2012-2022
Parsons (United States)
2015
Stanford University
2003-2012
University of Michigan
2012
UiT The Arctic University of Norway
2012
Washtenaw Community College
2012
Memorial Sloan Kettering Cancer Center
2009-2011
Babraham Institute
2001-2003
Autophagy is a degradative process that recycles long-lived and faulty cellular components. It linked to many diseases required for normal development. ULK1, mammalian serine/threonine protein kinase, plays key role in the initial stages of autophagy, though exact molecular mechanism unknown. Here we report identification novel complex containing ULK1 two additional factors, FIP200 ATG13, all which are essential starvation-induced autophagy. Both ATG13 critical correct localization...
In this study, we develop a simple assay to identify mitophagy inducers on the basis of use fluorescently tagged mitochondria that undergo colour change lysosomal delivery. Using assay, iron chelators as family compounds generate strong response. Iron chelation‐induced requires cells glycolysis, but does not require PINK1 stabilization or Parkin activation, and occurs in primary human fibroblasts well those isolated from Parkinson's patient with mutations. Thus, have identified characterized...
Autophagic turnover of mitochondria, termed mitophagy, is proposed to be an essential quality-control (QC) mechanism pathophysiological relevance in mammals. However, if and how mitophagy proceeds within specific cellular subtypes vivo remains unclear, largely because a lack tractable tools models. To address this, we have developed "mito-QC," transgenic mouse with pH-sensitive fluorescent mitochondrial signal. This allows the assessment architecture vivo. Using confocal microscopy,...
Autophagy is a cell-protective and degradative process that recycles damaged long-lived cellular components. Cancer cells are thought to take advantage of autophagy help them cope with the stress tumorigenesis; thus targeting an attractive therapeutic approach. However, there currently no specific inhibitors autophagy. ULK1, serine/threonine protein kinase, essential for initial stages autophagy, here we report two compounds, MRT67307 MRT68921, potently inhibit ULK1 ULK2 in vitro block...
The Vps34 (vacuolar protein sorting 34) class III PI3K (phosphoinositide 3-kinase) phosphorylates PtdIns (phosphatidylinositol) at endosomal membranes to generate PtdIns(3)P that regulates membrane trafficking processes via its ability recruit a subset of proteins possessing PtdIns(3)P-binding PX (phox homology) and FYVE domains. In the present study, we describe highly selective potent inhibitor Vps34, termed VPS34-IN1, inhibits with 25 nM IC50 in vitro, but does not significantly inhibit...
Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of macroautophagy/autophagy (especially mitophagy) protective effect IPC kidneys. induced autophagy renal tubular cells mice and suppressed subsequent ischemia-reperfusion injury (IRI). The was abolished by pharmacological inhibitors ablation Atg7 from kidney proximal tubules. Pretreatment with BECN1/Beclin1 peptide...
Article22 May 2018Open Access Transparent process LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages Anetta Härtlova MRC Protein Phosphorylation and Ubiquitylation Unit, University Dundee, UK Newcastle University, Newcastle-upon-Tyne, Search for more papers by this author Susanne Herbst Host-Pathogen Interactions Tuberculosis Laboratory, The Francis Crick Institute, London, Crick-GSK Biomedical LinkLabs, GlaxoSmithKline Pharmaceuticals R&D,...
Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson's disease. LRRK2-targeting strategies have primarily focused on type 1 inhibitors, which, however, limitations as inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report development LRRK2 proteolysis targeting chimeras (PROTACs), culminating in discovery degrader XL01126, an alternative strategy. Initial designs and screens PROTACs based...
Abstract Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive cells have high autophagic flux, identify an autophagy checkpoint whereby antigen receptor engagement inflammatory cytokines acutely repress by regulating amino acid transporter expression intracellular delivery. Activated with levels transporters low flux in amino-acid-replete conditions but rapidly reinduce when acids restricted. A census proteins...
Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances tolerance to various stresses. Recent studies indicate that class anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One the HDAC suberoylanilide hydroxamic acid (SAHA), currently being used treating cutaneous T-cell lymphoma under clinical trials multiple other cancer types, including glioblastoma. Here, we...
Mannose 6-phosphate receptors (MPRs) are transported from endosomes to the Golgi after delivering lysosomal enzymes endocytic pathway. This process requires Rab9 guanosine triphosphatase (GTPase) and putative tether GCC185. We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, VAMP3 is required for this MPR transport but not STX6-dependent TGN46 or cholera toxin early Golgi. Depletion STX10 leads missorting...
Article2 July 2015Open Access Source Data mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival Michael J Munson MRC Protein Phosphorylation Ubiquitylation Unit, College of Life Sciences, University Dundee, UK Search for more papers by this author George FG Allen Rachel Toth David G Campbell John M Lucocq School Medicine, St Andrews, Ian Ganley Corresponding Author Information Munson1, Allen1, Toth1, Campbell1, Lucocq2 1 1MRC 2School *Corresponding...
Mutations in PINK1 and Parkin result autosomal recessive Parkinson's disease (PD). Cell culture vitro studies have elaborated the PINK1-dependent regulation of defined how this dyad orchestrates elimination damaged mitochondria via mitophagy. phosphorylates ubiquitin at serine 65 (Ser65) an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting activation; however, physiological significance phosphorylation vivo mammals remains unknown. To address this, we...
Sustained nutrient (fuel) excess, as occurs during obesity and diabetes, has been linked to increased inflammation, impaired mitochondrial homeostasis, lipotoxicity, insulin resistance in skeletal muscle. Precisely how dysfunction is initiated whether it contributes this tissue remains a poorly resolved issue. Herein, we examine the contribution that an increase proinflammatory NFkB signalling makes towards regulation of bioenergetics, morphology, dynamics its impact upon action muscle cells...
Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of autophagy mitochondria, known as mitophagy. Here, we investigated role LRRK2, protein kinase frequently mutated PD, process vivo. Using mitophagy reporter mice, bearing either knockout LRRK2 or expressing pathogenic...
Mitophagy is a natural phenomenon and entails the lysosomal degradation of mitochondria by autophagy pathway. In recent years, development fluorescent pH-sensitive mitochondrial reporters has greatly facilitated monitoring mitophagy distinguishing between cytosolic or those delivered to acidic lysosomes. We recently published mito-QC reporter, which consists outer membrane-localised tandem mCherry-GFP tag. This allows quantification via increase in red-only mCherry signal that arises when...
Abstract Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin function. can also be turned over by autophagy, processes termed mitophagy pexophagy, respectively. However, despite their close relationship, it is not known if organelles under similar conditions, so, how this might coordinated molecularly. Here, we find that multiple selective autophagy pathways activated upon iron chelation show pexophagy occur a BNIP3L/NIX‐dependent manner. We reveal...