Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes

Daugaard, Mads; Nitsch, Roberto; Razaghi, Babak; McDonald, Lindsay; Jarrar, Ameer; Torrino, Stéphanie; Castillo-Lluva, Sonia; Rotblat, Barak; Li, Liheng; Malliri, Angeliki; Lemichez, Emmanuel; Mettouchi, Amel; Berman, Jason N.; Penninger, Josef; Sorensen, Poul H.

doi:10.1038/ncomms3180

Cited by 99 publications

(135 citation statements)

References 58 publications

(94 reference statements)

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“…Given the known role of oxidative stress in neurodegeneration and expression of HACE1 in brain (15), we measured ROS, antioxidant levels, and oxidative stress markers in brains of Hace1 KO mice. In line with our findings in other tissues (19), Hace1 KO brain tissue exhibited increased ROS levels (Fig. 3A).…”

Section: Hace1 Mediatessupporting

confidence: 81%

“…Recently, we found increased ROS levels in different peripheral tissues of Hace1 KO mice due to increased activity of ROS generating Rac1-dependent NADPH oxidase complexes (19). We show here that brains of Hace1 KO mice exhibit redox imbalance and increased oxidative stress but reduced NQO1 expression, a known NRF2 target gene and a marker of the antioxidative stress response (5,13).…”

Section: Discussionmentioning

confidence: 60%

“…This was not rescued by Apocynin or ML171, inhibitors of NADPH oxidase activity (Fig. S5D), suggesting that the reduced NRF2 activity occurs independently of NADPH oxidase activity (19). Similar to Hace1 KO MEFs, NRF2 accumulation was reduced under oxidative stress in mHTT-expressing cells (Fig.…”

Section: Hace1 Mediatesmentioning

confidence: 55%

“…wrote the paper. bound to Rac1-dependent NADPH oxidase complexes, and therefore reduces ROS generation by these complexes (19).…”

Section: Significancementioning

confidence: 99%

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HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rotblat

Southwell

Ehrnhoefer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oxidative stress plays a key role in late onset diseases including cancer and neurodegenerative diseases such as Huntington disease. Therefore, uncovering regulators of the antioxidant stress responses is important for understanding the course of these diseases. Indeed, the nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidative stress response, is deregulated in both cancer and neurodegeneration. Similar to NRF2, the tumor suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays a protective role against stress-induced tumorigenesis in mice, but its roles in the antioxidative stress response or its involvement in neurodegeneration have not been investigated. To this end we examined Hace1 WT and KO mice and found that Hace1 KO animals exhibited increased oxidative stress in brain and that the antioxidative stress response was impaired. Moreover, HACE1 was found to be essential for optimal NRF2 activation in cells challenged with oxidative stress, as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein synthesis, leading to lower tolerance against oxidative stress triggers. Strikingly, we found a reduction of HACE1 levels in the striatum of Huntington disease patients, implicating HACE1 in the pathology of Huntington disease. Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells provided protection against mutant Huntingtin-induced redox imbalance and hypersensitivity to oxidative stress, by augmenting NRF2 functions. These findings reveal that the tumor suppressor HACE1 plays a role in the NRF2 antioxidative stress response pathway and in neurodegeneration.

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Section: Hace1 Mediatessupporting

confidence: 81%

Section: Discussionmentioning

confidence: 60%

Section: Hace1 Mediatesmentioning

confidence: 55%

“…wrote the paper. bound to Rac1-dependent NADPH oxidase complexes, and therefore reduces ROS generation by these complexes (19).…”

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Rotblat

Southwell

Ehrnhoefer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…) and Tg(pod:Gal4;UAS:EGFP-rac1 T17N ), in which constitutively active and dominant negative forms of zebrafish Rac1 were tagged with GFP at the N terminus (8). In fact, Rac1 expression was mosaic in Tg(pod:Gal4;UAS:EGFP-rac1 G12V ) (Fig.…”

Section: G12vmentioning

confidence: 99%

Dosage-dependent role of Rac1 in podocyte injury

Wan

Lee

Zhou

2016

American Journal of Physiology-Renal Physiology

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Wan X, Lee M, Zhou W. Dosage-dependent role of Rac1 in podocyte injury. Am J Physiol Renal Physiol 310: F777-F784, 2016. First published January 20, 2016 doi:10.1152/ajprenal.00381.2015.-Activation of small GTPase Rac1 in podocytes is associated with rodent models of kidney injury and familial nephrotic syndrome. Induced Rac1 activation in podocytes in transgenic mice results in rapid transient proteinuria and foot process effacement, but not glomerular sclerosis. Thus it remains an open question whether abnormal activation of Rac1 in podocytes is sufficient to cause permanent podocyte damage. Using a number of transgenic zebrafish models, we showed that moderate elevation of Rac1 activity in podocytes did not impair the glomerular filtration barrier but aggravated metronidazole-induced podocyte injury, while inhibition of Rac1 activity ameliorated metronidazole-induced podocyte injury. Furthermore, a further increase in Rac1 activity in podocytes was sufficient to cause proteinuria and foot process effacement, which resulted in edema and lethality in juvenile zebrafish. We also found that activation of Rac1 in podocytes significantly downregulated the expression of nephrin and podocin, suggesting an adverse effect of Rac1 on slit diaphragm protein expression. Taken together, our data have demonstrated a causal link between excessive Rac1 activity and podocyte injury in a dosagedependent manner, and transgenic zebrafish of variable Rac1 activities in podocytes may serve as useful animal models for the study of Rac1-related podocytopathy.

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Increased ROS levels in mitochondrial outer membrane protein Mul1‐deficient oocytes result in abnormal preimplantation embryogenesis

Nakai,

Fukushima,

Yamamoto

et al. 2024

FEBS Letters

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Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N‐acetyl‐l‐cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1‐deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1‐deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.

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Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes

Cited by 99 publications

References 58 publications

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Dosage-dependent role of Rac1 in podocyte injury

Increased ROS levels in mitochondrial outer membrane protein Mul1‐deficient oocytes result in abnormal preimplantation embryogenesis

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