Dynamic Interaction of USP14 with the Chaperone HSC70 Mediates Crosstalk between the Proteasome, ER Signaling, and Autophagy

USP14 is a deubiquitinating enzyme associated with the proteasome that is important for protein degradation. Here we show that upon proteasomal inhibition or expression of the mutant W58A38 USP14, association of USP14 with the 19S regulatory particle is disrupted. MS-based interactomics revealed an interaction of USP14 with the chaperone, HSC70 in neuroblastoma cells. Proteasome inhibition enhanced binding of USP14 to HSC70, but also to XBP1u and IRE1α proteins, demonstrating a role in the unfolded protein response. Striatal neurons expressing mutant huntingtin exhibited reduced USP14 and HSC70 levels, whilst inhibition of HSC70 downregulated USP14. Furthermore, proteasome inhibition or the use of mutant W58A-USP14 facilitated the interaction of USP14 with the autophagy protein, GABARAP. Functionally, overexpression of W58A-USP14 increased GABARAP positive autophagosomes in striatal neurons and this was abrogated using the HSC70 inhibitor, VER-155008. Modulation of the USP14-HSC70 axis by various drugs may represent a potential therapeutic target in HD to beneficially influence multiple proteostasis pathwaysPeer reviewe

Destabilization of the Outer and Inner Mitochondrial Membranes by Core and Linker Histones

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Peroxisome proliferator-activated receptor-γ coactivator-1α mediates neuroprotection against excitotoxic brain injury in transgenic mice: Role of mitochondria and X-linked inhibitor of apoptosis protein

Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1α in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1α in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1α transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC-1α transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild-type mice but significantly less so in PGC-1α transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1α overexpression can induce a delay in cell death. Immunoblotting showed that X-linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1α transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1α overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP

Hepatocyte Growth Factor Activator Inhibitor-1 Is Induced by Bone Morphogenetic Proteins and Regulates Proliferation and Cell Fate of Neural Progenitor Cells

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Combined effects of cover crops, mulch, zero-tillage and resistant varieties on Striga asiatica (L.) Kuntze in rice-maize rotation systems

In low-input rice-maize rotation systems in the hills of central Madagascar, farmers deal with erratic rainfall, poor soils, high soil erosion risks and infestation by the parasitic weed Striga asiatica (L.) Kuntze. Practices combining zero-tillage with permanent soil cover by intercropped legumes and crop residue mulches — known as Conservation Agriculture (CA)— are proposed as remedy against soil and climatic constraints. Implications of these practices for S. asiatica are unknown. A 4-season factorial experiment compared the current farmer practice of rice − maize rotation, involving seasonal tillage and crop residue removal (CONV), with three rice − maize rotation systems following CA with different cover crops, i.e. Vigna unguiculata (cowpea) and Mucuna pruriens (CACM), Vigna umbellata (ricebean) (CARB), and Stylosanthes guianensis (CAST). Performance of two rice varieties, NERICA-4 and −9, with partial S. asiatica resistance, were compared with the locally popular B22. Parasite emergence time, numbers, and seed bank sizes were recorded. In all CA practices S. asiatica infection was significantly reduced. Best results were obtained with Stylosanthes guianensis (CAST). This species also suppressed ordinary weeds much better than other cover crops. With CAST, average parasite emergence was delayed by 7.5 days (in rice) and 6.3 days (in maize) and infection levels were reduced by 79% (in rice) and 92% (in maize) compared to the conventional farmer practice (CONV). NERICA varieties delayed S. asiatica emergence by 5.7 days (NERICA-9) and 9.7 days (NERICA-4) and reduced infection levels by 57% (NERICA-9) and 91% (NERICA-4) compared to B22. In maize the residual effect of resistance of NERICA-4 resulted in a delay of 7.5 days in S. asiatica emergence and a reduction of 60% in parasite numbers. The best combinations delay S. asiatica emergence by 17.8 days (CAST + NERICA-9) and 19.1 days (CARB + NERICA-4) and reduce the parasite infection levels by 96% (CAST + NERICA-9 or −4) to 98% (CARB + NERICA-4) in rice, compared to CONV + B22. After two full rice-maize rotation cycles S. asiatica seed numbers in the soil (0–10 cm) were 76% (CACM), 78% (CAST) and 86% (CARB) lower than under CONV. Even the combination of zero-tillage, crop residue mulching, cover crops and resistant rice varieties does not entirely prevent S. asiatica parasitism and seed bank increase. Additional measures, targeted to escaping weeds, would be required for fully effective and long-term control