Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis

Li, Nan; Jacko, Anastasia M.; Tan, Jiangning; Wang, Dan; Zhao, Jing; Kass, Daniel J.; Ma, Hu; Zhao, Yutong

doi:10.1038/srep33116

Cited by 37 publications

(29 citation statements)

References 37 publications

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“…Uch37 has been implicated in DNA replication and cell cycle [141], TGF-β signaling [142–145], WNT signaling via Tcf7 [146], longevity [147], cell migration and invasion [148], and the reversal of ubiquitination of proteasome subunits [138]. It is difficult to resolve common themes from the physiological studies reported to date.…”

Section: Physiological Functionmentioning

confidence: 99%

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Poot

Tian

Finley

2017

Journal of Molecular Biology

103

115

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Three deubiquitinating enzymes–Rpn11, Usp14, and Uch37–are associated with the proteasome regulatory particle. These enzymes allow proteasomes to remove ubiquitin from substrates before they are translocated into the core particle to be degraded. Although the translocation channel is too narrow for folded proteins, the force of translocation unfolds them mechanically. As translocation proceeds, ubiquitin chains bound to substrate are drawn to the channel’s entry port, where they can impede further translocation. Rpn11, situated over the port, can remove these chains without compromising degradation because substrates must be irreversibly committed to degradation before Rpn11 acts. This coupling between deubiquitination and substrate degradation is ensured by the Ins-1 loop of Rpn11, which controls ubiquitin access to its catalytic site. In contrast to Rpn11, Usp14 and Uch37 can rescue substrates from degradation by promoting substrate dissociation from the proteasome prior to the commitment step. Uch37 is unique in being a component of both the proteasome and a second multisubunit assembly, the INO80 complex. However, only recruitment into the proteasome activates Uch37. Recruitment to the proteasome likewise activates Usp14. However, the influence of Usp14 on the proteasome depends on the substrate, due to its marked preference for proteins that carry multiple ubiquitin chains. Usp14 exerts complex control over the proteasome, suppressing proteasome activity even when inactive in deubiquitination. A major challenge for the field will be to elucidate the specificities of Rpn11, Usp14, and Uch37 in greater depth, employing not only model in vitro substrates, but their endogenous targets.

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Section: Physiological Functionmentioning

confidence: 99%

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Poot

Tian

Finley

2017

Journal of Molecular Biology

103

115

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“…UCHL5 encodes ubiquitin carboxyl-terminal hydrolase-L5 a deubiquitinating enzyme that stabilizes several Smad proteins and TGFBR1, key components of the TGF-beta1 signalling pathway [31,32] .…”

Section: Exemplar Regionsmentioning

confidence: 99%

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Burren

Garćıa

Javierre

et al. 2017

Preprint

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BackgroundAutoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes.ResultsWithin four hours, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach.ConclusionsOur systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.

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“…Con, control; Dia, diabetes; Dia+4-PBA, diabetes group treated with 4-PBA; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SEM, standard error of the mean F I G U R E 5 Expression of ERAD components in the cerebral cortex of rats. 32 This is the first study to show the alteration in the expression of the UCHL5 protein in the brain of diabetic rats, and its role remains to be explored. Expression values were represented as fold change over control on an arbitrary scale after normalization with β-actin.…”

Section: Discussionmentioning

confidence: 92%

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

Karnam

Reddy

Chitra

2018

J of Cellular Biochemistry

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The ubiquitin‐proteasome system (UPS) has been implicated in the pathogenesis of many neurodegenerative diseases. Endoplasmic reticulum (ER) stress is shown to play a pathological role in the development of diabetes and its complications. Hence, the current study is aimed to investigate the role of UPS and ER stress in the cerebral cortex of diabetic rats and examine the therapeutic effect of 4‐phenylbutyric acid (4‐PBA), an ER stress inhibitor. Male Sprague‐Dawley rats were divided into three groups: control, diabetes, and diabetes plus 4‐PBA treatment group. Diabetes was induced by single intraperitoneal streptozotocin injection (37 mg/kg body weight [bw]), and 4‐PBA was administered (40 mg/kg bw/d, intraperitoneal) for 2 months, starting from 2 months of diabetes induction. At the end of 4 months, cerebral cortex was collected for analysis. Declined proteasome activity and ubiquitin C‐terminal hydrolase (UCH)‐L1 expression, increased ubiquitinated proteins, and apoptosis were observed in the diabetic rats. The expression of the ubiquitin‐activating enzyme E1, UCHL5, and ER stress markers (ATF6, pPERK, and CHOP) was markedly elevated, whereas the expression of ER‐associated protein degradation (ERAD) components was downregulated in the diabetic rats. 4‐PBA intervention attenuated ER stress, alterations in UPS, and ERAD components in diabetic rats. Importantly, neuronal apoptosis was lowered in 4‐PBA‐treated diabetic rats. Our observations demonstrate that altered UPS could be one of the underlying mechanisms of neuronal apoptosis in diabetes and chemical chaperones such as 4‐PBA could be potential candidates for preventing these alterations under hyperglycemic conditions.

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Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis

Cited by 37 publications

References 37 publications

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Meddling with Fate: The Proteasomal Deubiquitinating Enzymes

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Ubiquitin‐proteasome system and ER stress in the brain of diabetic rats

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