A5084050236- Autophagy in Disease and Therapy
- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Cellular transport and secretion
- Parkinson's Disease Mechanisms and Treatments
- Cannabis and Cannabinoid Research
- Adenosine and Purinergic Signaling
- Calcium signaling and nucleotide metabolism
- Immune Cell Function and Interaction
- Ubiquitin and proteasome pathways
- vaccines and immunoinformatics approaches
- Mosquito-borne diseases and control
- RNA modifications and cancer
- Influenza Virus Research Studies
- Neurological disorders and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
Australian Regenerative Medicine Institute
2021-2025
Monash University
2021-2025
Research Network (United States)
2022-2025
Walter and Eliza Hall Institute of Medical Research
2022-2025
The University of Melbourne
2022-2025
Institute of Infection and Immunity
2024
Cargo sequestration is a fundamental step of selective autophagy in which cells generate double-membrane structure termed an "autophagosome" on the surface cargoes. NDP52, TAX1BP1, and p62 bind FIP200, recruits ULK1/2 complex to initiate autophagosome formation How OPTN initiates during remains unknown despite its importance neurodegeneration. Here, we uncover unconventional path PINK1/Parkin mitophagy initiation by that does not begin with FIP200 binding or require kinases. Using...
Activation of PINK1 and Parkin in response to mitochondrial damage initiates a that includes phosphorylation RAB7A at Ser72. Rubicon is binding negative regulator autophagy. The structure the Rubicon:RAB7A complex suggests Ser72 would block binding. Indeed, vitro by TBK1 abrogates Pacer, positive autophagy, has an RH domain with basic triad predicted bind introduced phosphate. Consistent this, Pacer-RH binds phosho-RAB7A but not unphosphorylated RAB7A. In cells, depolarization reduces...
Abstract Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding 1) adaptors NAP1 (NAK-associated protein SINTBAD (similar to...
Selective autophagy is a lysosomal degradation pathway that critical for maintaining cellular homeostasis by disposing of harmful material. While the mechanisms which soluble cargo receptors recruit machinery are becoming increasingly clear, principles governing how organelle-localized transmembrane initiate selective remain poorly understood. Here, we demonstrate can autophagosome biogenesis not only recruiting upstream FIP200/ULK1 complex but also via WIPI-ATG13 complex. This latter...
The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 -C2) have vital roles in macroautophagy endosomal maturation, respectively. We elucidated a structural pathway of enzyme activation through cryo-EM analysis PI3KC3-C1. inactive conformation the VPS15 pseudokinase stabilizes conformation, sequestering its N -myristate N-lobe pseudokinase. Upon activation, myristate is liberated such that VPS34 lipid catalyzes PI3P production on membranes. domain binds tightly to...
Breakdown of mitochondrial proteostasis activates quality control pathways including the unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond up-regulation chaperones proteases, we have a limited understanding how UPRmt remodels restores damaged proteomes. Here, developed functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect UPRmt's role in maintaining during stress. We find essential roles for both protecting...
Abstract The unc-51-like kinase protein complex (ULK1C) is the most upstream and central player in initiation of macroautophagy mammals. Here, cryo-EM structure human ULK1C core was determined at amino acid residue-level resolution. A moderate resolution with another autophagy complex, class III phosphatidylinositol 3-kinase I (PI3KC3-C1) also determined. two complexes co-assemble through extensive contacts between FIP200 scaffold subunit VPS15, ATG14, BECN1 subunits PI3KC3-C1....
Abstract Influenza B viruses (IBVs) cause substantive morbidity and mortality, yet immunity towards IBVs remains understudied. CD8 + T-cells provide broadly cross-reactive alleviate disease severity by recognizing conserved epitopes. Despite the IBV burden, only 18 IBV-specific T-cell epitopes restricted 5 HLAs have been identified currently. A broader array of is needed to develop effective based vaccines. Here we identify 9 highly HLA-B*07:02, HLA-B*08:01 HLA-B*35:01. Memory tetramer are...
Abstract Defects in neuronal mitophagy have been linked to neurodegenerative diseases including Parkinson’s disease. However, despite the importance of homeostasis, mechanistic basis for neurodegeneration when is defective unclear. Here, using human neurons, we discover that presynapses are pit stops damaged axonal mitochondria. We show while mitochondrial damage and PINK1/Parkin activation events distributed throughout axons, initiation autophagosome formation restricted presynapses, which...
Abstract Cargo sequestration is a fundamental step of selective autophagy in which cells generate double membrane structure termed an autophagosome on the surface cargoes. NDP52, TAX1BP1 and p62 bind FIP200 recruits ULK1/2 complex to initiate formation How OPTN initiates during remains unknown despite its importance neurodegeneration. Here, we uncover unconventional path PINK1/Parkin mitophagy initiation by that does not begin with binding nor require kinases. Using gene-edited cell lines...
SUMMARY Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PINK1/Parkin-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 adaptors NAP1 SINTBAD restrict initiation of OPTN-driven competing with OPTN TBK1. Conversely, they promote NDP52-driven recruiting to NDP52...
SUMMARY Activation of PINK1 and Parkin in response to mitochondrial damage initiates a cytoprotective mitophagy that includes phosphorylation RAB7A at Ser72. Rubicon is binding protein acts as negative regulator autophagy. The structure the Rubicon-RAB7A complex suggests Ser72 would block binding. Indeed, vitro by TBK1 abrogates Pacer, positive autophagy, has an RH domain with basic triad predicted bind introduced phosphate. Consistent this, Pacer-RH binds phosho-RAB7A but not...
ABSTRACT Breakdown of mitochondrial proteostasis activates quality control pathways including the unfolded protein response (UPR mt ) and PINK1/Parkin mitophagy. However, beyond upregulation chaperones proteases, we have a limited understanding how UPR remodels restores damaged mito-proteomes. Here, developed functional proteomics framework, termed MitoPQ ( Mito chondrial P roteostasis Q uantification), to dissect ’s role in maintaining during stress. We discover essential roles for both...