SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation

Jiang, Tiancai; Zou, Jiang-Bo; Zhu, Qianqian; Liu, Cui Hua; Wang, Guangfei; Du, Tingting; Luo, Zi-Yu; Guo, Fang; Zhou, Luming; Liu, Juanjuan; Zhang, Wensheng; Shu, Yousheng; Yu, Li; Ronai, Ze’ev A.; Matsuzawa, Shu‐ichi; Goldberg, Alfred L.; Qiu, Xiao‐Bo

doi:10.1073/pnas.1901039116

Cited by 44 publications

(45 citation statements)

References 45 publications

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“…In any event, the mechanism involving LC3B ubiquitination and degradation revealed by our study is consistent with the activity of BIRC6 as an E2/E3 enzyme. While our manuscript was in preparation, another study showed that BIRC6 targeted LC3B-I for proteasomal degradation, and that BIRC6 itself was subject to proteasomal degradation promoted by the ubiquitin ligase RNF41/NRDP1 (neuregulin receptor degradation protein-1) and inhibited by CACYBP/SIP (calcyclin-binding protein/siah-1 interacting protein) (Jiang et al, 2019). Taken together, these findings reveal the existence of a complex regulatory network for the control of LC3B levels.…”

Section: Discussionmentioning

confidence: 99%

Negative regulation of autophagy by UBA6-BIRC6–mediated ubiquitination of LC3

Jia

Bonifacino

2019

eLife

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Although the process of autophagy has been extensively studied, the mechanisms that regulate it remain insufficiently understood. To identify novel autophagy regulators, we performed a whole-genome CRISPR/Cas9 knockout screen in H4 human neuroglioma cells expressing endogenous LC3B tagged with a tandem of GFP and mCherry. Using this methodology, we identified the ubiquitin-activating enzyme UBA6 and the hybrid ubiquitin-conjugating enzyme/ubiquitin ligase BIRC6 as autophagy regulators. We found that these enzymes cooperate to monoubiquitinate LC3B, targeting it for proteasomal degradation. Knockout of UBA6 or BIRC6 increased autophagic flux under conditions of nutrient deprivation or protein synthesis inhibition. Moreover, UBA6 or BIRC6 depletion decreased the formation of aggresome-like induced structures in H4 cells, and α-synuclein aggregates in rat hippocampal neurons. These findings demonstrate that UBA6 and BIRC6 negatively regulate autophagy by limiting the availability of LC3B. Inhibition of UBA6/BIRC6 could be used to enhance autophagic clearance of protein aggregates in neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Negative regulation of autophagy by UBA6-BIRC6–mediated ubiquitination of LC3

Jia

Bonifacino

2019

eLife

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“…These results thus demonstrated that USP10 depletion reduced the levels of endogenous LC3B, an effect that was opposite to that caused by depletion of the ubiquitinating enzymes UBA6 or BIRC6 (11,12). LC3B can be turned over by both lysosomal (16) and proteasomal degradation (11)(12)(13). To examine which pathway was responsible for the reduced levels of LC3B in USP10deficient cells, we tested the effect of specific inhibitors.…”

Section: Resultsmentioning

confidence: 94%

“…We and others found that LC3B is monoubiquitinated by the concerted action of the UBA6 E1 ubiquitin (Ub)-activating enzyme and the BIRC6 hybrid E2 ubiquitin-conjugating enzyme/E3 Ub ligase ( 11 , 12 ), and polyubiquitinated by the von Hippel–Lindau (VHL) tumor suppressor E3 Ub ligase ( 13 ). Both monoubiquitination and polyubiquitination lead to proteasomal degradation of LC3B, with consequent decrease in autophagic activity ( 11 , 12 , 13 ). In general, protein ubiquitination is reversed by Ub removal catalyzed by a family of isopeptidases known as deubiquitinating enzymes (DUBs) ( 14 ).…”

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confidence: 99%

The ubiquitin isopeptidase USP10 deubiquitinates LC3B to increase LC3B levels and autophagic activity

Jia

Bonifacino

2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…We also observed the synergetic protective effect of baicalein and MARCH5 on H 2 O 2 induced cardiotoxicity (Figure C–E). Most recent studies have revealed that ubiquitination can promote apoptosis, we then tested the modification of MARCH5 by ubiquitin. As shown in Figure B, the mount of ubiquitin‐MARCH5 noticeable increased compared with control under oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

Baicalein inhibits mitochondrial apoptosis induced by oxidative stress in cardiomyocytes by stabilizing MARCH5 expression

Xiao

et al. 2019

J Cellular Molecular Medi

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Mitochondrial homoeostasis is required for normal cell physiology, 1 abnormal mitochondrial dynamics and mitophagy participate in the regulation of pathogenesis of heart diseases. 2-5 Excessive mitochondrial fission promotes cell apoptosis; inversely, mitochondrial fusion is able to inhibit apoptosis, 1 while growing number of evidence reveals that unbalanced mitophagy also can induce cell apoptosis. 3,6,7 The membrane-associated RING-CH (MARCH) proteins belong to the RING finger protein family of E3 ubiquitin ligases. MARCH5, one of MARCH protein family, is mainly localized on the mitochondrial outer membrane. MARCH5 has been considered to play roles in immune regulation, protein quality control and membrane Abstract Abnormal mitochondrial fission and mitophagy participate in the pathogenesis of many cardiovascular diseases. Baicalein is a key active component in the roots of traditional Chinese medicinal herb Scutellaria baicalensis Georgi. It has been reported that baicalein can resist cardiotoxicity induced by several stress, but the mechanisms of baicalein operate in the protection of cardiomyocytes need to be researched further. Here we report that baicalein can promote cell survival under oxidative stress by up-regulating the expression level of MARCH5 in cardiomyocytes. Pre-treatment cells or mice with baicalein can stabilize the expression of MARCH5, which plays a crucial role in the regulation of mitochondrial network and mitophagy. Overexpressed MARCH5 is able to against H 2 O 2 and ischaemia/reperfusion (I/R) stress by suppressing mitochondrial fission and enhancing mitophagy, and then attenuate cells apoptosis. Altogether, our present study investigated that baicalein exerts a protective effect through regulating KLF4-MARCH5-Drp1 pathway, our research also provided a novel theoretical basis for the clinical application of baicalein. K E Y W O R D S apoptosis, baicalein, cardioprotection, MARCH5, mitophagy, oxidative stress

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SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation

Cited by 44 publications

References 45 publications

Negative regulation of autophagy by UBA6-BIRC6–mediated ubiquitination of LC3

Negative regulation of autophagy by UBA6-BIRC6–mediated ubiquitination of LC3

The ubiquitin isopeptidase USP10 deubiquitinates LC3B to increase LC3B levels and autophagic activity

Baicalein inhibits mitochondrial apoptosis induced by oxidative stress in cardiomyocytes by stabilizing MARCH5 expression

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