Search

Your search keyword '"Ng DCH"' showing total 3 results
Start Over Author "Ng DCH" Publication Year Range Last 3 years
3 results on '"Ng DCH"'

1. PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4

Author

Nguyen-Dien, GT, Townsend, B, Kulkarni, PG, Kozul, K-L, Ooi, SS, Eldershaw, DN, Weeratunga, S, Liu, M, Jones, MJK, Millard, SS, Ng, DCH, Pagano, M, Bonfim-Melo, A, Schneider, T, Komander, D, Lazarou, M, Collins, BM, Pagan, JK, Nguyen-Dien, GT, Townsend, B, Kulkarni, PG, Kozul, K-L, Ooi, SS, Eldershaw, DN, Weeratunga, S, Liu, M, Jones, MJK, Millard, SS, Ng, DCH, Pagano, M, Bonfim-Melo, A, Schneider, T, Komander, D, Lazarou, M, Collins, BM, and Pagan, JK

Abstract

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.

Published
2024

2. Stress pathway outputs are encoded by pH-dependent clustering of kinase components.

Author

Didan Y, Ghomlaghi M, Nguyen LK, and Ng DCH

Subjects
Hydrogen-Ion Concentration, Humans, Mitogen-Activated Protein Kinase 9 metabolism, Mitogen-Activated Protein Kinase 9 genetics, Stress, Physiological, Signal Transduction, Animals, Optogenetics, MAP Kinase Signaling System, MAP Kinase Kinase Kinase 5 metabolism, MAP Kinase Kinase Kinase 5 genetics
Abstract

Signal processing by intracellular kinases controls near all biological processes but how signal pathway functions evolve with changed cellular context is poorly understood. Functional specificity of c-Jun N-terminal Kinases (JNK) are partly encoded by signal strength. Here we reveal that intracellular pH (pHi) is a significant component of the JNK network and defines signal response to specific stimuli. We show pHi regulates JNK activity in response to cell stress, with the relationship between pHi and JNK activity dependent on specific stimuli and upstream kinases activated. Using the optogenetic clustering tag CRY2, we show that an increase in pHi promotes the light-induced phase transition of ASK1 to augment JNK activation. While increased pHi similarly promoted CRY2-tagged JNK2 to form light-induced condensates, this attenuated JNK activity. Mathematical modelling of feedback signalling incorporating pHi and differential contributions by ASK1 and JNK2 condensates was sufficient to delineate signal responses to specific stimuli. Taking pHi and ASK1/JNK2 signal contributions into consideration may delineate oncogenic versus tumour suppressive JNK functions and cancer cell drug responses., (© 2024. The Author(s).)

Published
2024
Full Text
View/download PDF

3. Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease.

Author

Ding Q, Kesavan K, Lee KM, Wimberger E, Robertson T, Gill M, Power D, Chang J, Fard AT, Mar JC, Henderson RD, Heggie S, McCombe PA, Jeffree RL, Colditz MJ, Hilliard MA, Ng DCH, Steyn FJ, Phillips WD, Wolvetang EJ, Ngo ST, and Noakes PG

Subjects
Humans, LDL-Receptor Related Proteins metabolism, Receptors, Cholinergic metabolism, Signal Transduction, Agrin metabolism, Motor Neuron Disease
Abstract

A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin (n-agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n-agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n-agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n-agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND., (© 2022. The Author(s).)

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results