Elevated post-ischemic ubiquitination results from suppression of deubiquitinase activity and not proteasome inhibition

Kahles, Timo; Poon, Carrie; Qian, Liping; Palfini, Victoria; Srinivasan, Shanmukha Priya; Swaminathan, Shilpa; Blanco, Ismary; Rodney-Sandy, Reunet; Iadecola, Costantino; Zhou, Ping; Hochrainer, Karin

doi:10.1007/s00018-020-03625-5

Cited by 9 publications

(10 citation statements)

References 84 publications

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“…24,25 Deubiquitinase inhibition has been considered an endogenous protective mechanism to reduce neuronal proteins from oxidative damage. 24 However, this opinion is controversial since increased expression and activity of several ubiquitin ligases and associated proteins present neuroprotective effects after cerebral ischaemia, such as STUB1, NEDD4, ITCH and NDFIP1. 25 The indicated Myc-tagged FL or truncated mutation constructs were co-transfected with Flag-MDM2 primary rat neurons.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…I/R generally increases intraneuronal levels of ubiquitinated proteins, since ischaemia‐derived free radicals can suppress the activities of deubiquitinases 24,25 . Deubiquitinase inhibition has been considered an endogenous protective mechanism to reduce neuronal proteins from oxidative damage 24 . However, this opinion is controversial since increased expression and activity of several ubiquitin ligases and associated proteins present neuroprotective effects after cerebral ischaemia, such as STUB1, NEDD4, ITCH and NDFIP1 25 .…”

Section: Discussionmentioning

confidence: 99%

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LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

Wang

et al. 2021

J Cellular Molecular Medi

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Long non-coding RNA (lncRNA) MIAT (myocardial infarction associated transcript) has been characterized as a functional lncRNA modulating cerebral ischaemic/reperfusion (I/R) injury. However, the underlying mechanisms remain poorly understood.This study explored the functional partners of MIAT in primary rat neurons and their regulation on I/R injury. Sprague-Dawley rats were used to construct middle cerebral artery occlusion (MCAO) models. Their cerebral cortical neurons were used for in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) models. Results showed that MIAT interacted with EGLN2 in rat cortical neurons. MIAT overexpression or knockdown did not alter EGLN2 transcription. In contrast, MIAT overexpression increased EGLN2 stability after I/R injury via reducing its ubiquitin-mediated degradation. EGLN2 was a substrate of MDM2, a ubiquitin E3 ligase. MDM2 interacted with the N-terminal of EGLN2 and mediated its K48-linked poly-ubiquitination, thereby facilitating its proteasomal degradation. MIAT knockdown enhanced the interaction and reduced EGLN2 stability. MIAT overexpression enhanced infarct volume and induced a higher ratio of neuronal apoptosis. EGLN2 knockdown significantly reversed the injury. MIAT overexpression reduced oxidative pentose phosphate pathway flux and increased oxidized/reduced glutathione ratio, the effects of which were abrogated by EGLN2 knockdown. In conclusion, MIAT might act as a stabilizer of EGLN2 via reducing MDM2 mediated K48 poly-ubiquitination. MIAT-EGLN2 axis exacerbates I/R injury via altering redox homeostasis in neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

Wang

et al. 2021

J Cellular Molecular Medi

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“…Ubiquitination is an important posttranslational modification for intracellular proteins and has pleiotropic biological Ubiquitination facilities the rapid turnover of ubiquitinated substrates and cooperates with deubiquitination to regulate the dynamic equilibrium of intracellular proteins [53]. It is wellknown that the protein homeostasis is rapidly disrupted by cerebral I/R injury and in turn contributes to the progression of neurological dysfunction [54,55]. The ubiquitin-proteasome system helps to maintain protein homeostasis in eukaryotic cells through promoting the timely degradation of unnecessary or damaged proteins (e.g., misfolded proteins and oxidized proteins), and it is responsible for the degradation of 80-90% of all intracellular proteins [30,56].…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin‐Specific Protease 29 Exacerbates Cerebral Ischemia‐Reperfusion Injury in Mice

Hou

Shen

Wan

et al. 2021

Oxidative Medicine and Cellular Longevity

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Oxidative stress and apoptosis contribute to the progression of cerebral ischemia/reperfusion (I/R) injury. Ubiquitin-specific protease 29 (USP29) is abundantly expressed in the brain and plays critical roles in regulating oxidative stress and cell apoptosis. The purpose of the present study is to investigate the role and underlying mechanisms of USP29 in cerebral I/R injury. Neuron-specific USP29 knockout mice were generated and subjected to cerebral I/R surgery. For USP29 overexpression, mice were stereotactically injected with the adenoassociated virus serotype 9 vectors carrying USP29 for 4 weeks before cerebral I/R. And primary cortical neurons were isolated and exposed to oxygen glucose deprivation/reperfusion (OGD/R) stimulation to imitate cerebral I/R injury in vitro. USP29 expression was elevated in the brain and primary cortical neurons upon I/R injury. Neuron-specific USP29 knockout significantly diminished, whereas USP29 overexpression aggravated cerebral I/R-induced oxidative stress, apoptosis, and neurological dysfunction in mice. In addition, OGD/R-induced oxidative stress and neuronal apoptosis were also attenuated by USP29 silence but exacerbated by USP29 overexpression in vitro. Mechanistically, neuronal USP29 enhanced p53/miR-34a-mediated silent information regulator 1 downregulation and then promoted the acetylation and suppression of brain and muscle ARNT-like protein, thereby aggravating oxidative stress and apoptosis upon cerebral I/R injury. Our findings for the first time identify that USP29 upregulation during cerebral I/R may contribute to oxidative stress, neuronal apoptosis, and the progression of cerebral I/R injury and that inhibition of USP29 may help to develop novel therapeutic strategies to treat cerebral I/R injury.

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“…(2021). The group showed that accumulation of K48 and K63 ubiquitin after ischemia reperfusion was caused primarily by redox inhibition of DUBs instead of inhibition of the proteasome ( 214 ). Although the DUBs involved in this pathway were not identified, the determination that redox regulation of intracellular DUBs and not proteasomal inhibition was responsible for polyubiquitin accumulation generates numerous opportunities for new lines of research into postischemic ubiquitination and human health ( 214 ).…”

Section: Regulation Of Dub Activitymentioning

confidence: 99%

Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

Snyder

Silva

2021

Journal of Biological Chemistry

136

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Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein–protein interaction, posttranslational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.

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Elevated post-ischemic ubiquitination results from suppression of deubiquitinase activity and not proteasome inhibition

Cited by 9 publications

References 84 publications

LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

LncRNA MIAT enhances cerebral ischaemia/reperfusion injury in rat model via interacting with EGLN2 and reduces its ubiquitin‐mediated degradation

Ubiquitin‐Specific Protease 29 Exacerbates Cerebral Ischemia‐Reperfusion Injury in Mice

Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

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