Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2

Zhou, Zhangsen; Li, Meixin; Liu, Jie; Jiao, Hengwu; Xia, Jing-Ming; Shi, Xiongjie; Zhao, Huabin; Chu, Liping; Liu, Jingrong; Qi, Wei; Luo, Jie; Song, Bei

doi:10.1038/s41467-019-14231-w

Cited by 15 publications

(11 citation statements)

References 55 publications

(57 reference statements)

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“…Thioesterase Activity Is Possessed by DUBs with Isopeptidase and Esterase Activity. It has been reported that ubiquitination can also extend to cysteine residues where the linkage chemistry is a thioester bond (9,37). It remains unknown if DUBs can also cleave this linkage chemistry.…”

Section: Resultsmentioning

confidence: 99%

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

Cesare

López

Mabbitt

et al. 2021

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

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The reversibility of ubiquitination by the action of deubiquitinating enzymes (DUBs) serves as an important regulatory layer within the ubiquitin system. Approximately 100 DUBs are encoded by the human genome, and many have been implicated with pathologies, including neurodegeneration and cancer. Non-lysine ubiquitination is chemically distinct, and its physiological importance is emerging. Here, we couple chemically and chemoenzymatically synthesized ubiquitinated lysine and threonine model substrates to a mass spectrometry-based DUB assay. Using this platform, we profile two-thirds of known catalytically active DUBs for threonine esterase and lysine isopeptidase activity and find that most DUBs demonstrate dual selectivity. However, with two anomalous exceptions, the ovarian tumor domain DUB class demonstrates specific (iso)peptidase activity. Strikingly, we find the Machado–Joseph disease (MJD) class to be unappreciated non-lysine DUBs with highly specific ubiquitin esterase activity rivaling the efficiency of the most active isopeptidases. Esterase activity is dependent on the canonical catalytic triad, but proximal hydrophobic residues appear to be general determinants of non-lysine activity. Our findings also suggest that ubiquitin esters have appreciable cellular stability and that non-lysine ubiquitination is an integral component of the ubiquitin system. Its regulatory sophistication is likely to rival that of canonical ubiquitination.

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Section: Resultsmentioning

confidence: 99%

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

Cesare

López

Mabbitt

et al. 2021

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

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“…Then, as the rate-limiting enzyme of the pathway, hydroxy-methylglutaryl-CoA reductase (HMG-CoAR) converts HMG-CoA to mevalonate. HMG-CoAR contains a conserved SSD, which is characterized by five membrane-spanning α-helices ( Finco et al, 2015 ; Guo et al, 2018 ; Wangeline and Hampton, 2020 ) and is necessary for its attachment to the protein Insig on ER membrane as well as for the regulation of its degradation ( Theesfeld and Hampton, 2013 ; Zhou et al, 2020 ). In the following steps, mevalonate is converted successively to isopentenyl pyrophosphate, squalene and lanosterol.…”

Section: Hedgehog Signaling Regulates Cholesterolmentioning

confidence: 99%

Cholesterol and Hedgehog Signaling: Mutual Regulation and Beyond

Tang

2022

Front. Cell Dev. Biol.

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The Hedgehog (HH) signaling is one of the key agents that govern the precisely regulated developmental processes of multicellular organisms in vertebrates and invertebrates. The HH pathway in the receiving cell includes Patched1, a twelve-pass transmembrane receptor, and Smoothened, a seven-transmembrane G-protein coupled receptor (GPCR), and the downstream GLI family of three transcriptional factors (GLI1-GLI3). Mutations of HH gene and the main components in HH signaling are also associated with numerous types of diseases. Before secretion, the HH protein undergoes post-translational cholesterol modification to gain full activity, and cholesterol is believed to be essential for proper HH signaling transduction. In addition, results from recent studies show the reciprocal effect that HH signaling functions in cholesterol metabolism as well as in cholesterol homeostasis, which provides feedback to HH pathway. Here, we hope to provide new insights into HH signaling function by discussing the role of cholesterol in HH protein maturation, secretion and HH signaling transduction, and the potential role of HH in regulation of cholesterol as well.

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“…It has been proved that Insig2 is ubiquitylated by gp78 17 , 19 . To verify this regulatory mechanism of Insig2 by gp78 in TGM, a series of experiments were applied.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of lipogenic gene expression is mediated by SREBP following degradation of its inhibitors Insulin Induced Gene 1/2 (Insig1 and Insig2) 14 - 16 . Glycoprotein 78 (gp78), a rate-limiting E3 ubiquitin ligase regulator of lipid metabolism, plays a critical role in the degradation of Insig1/2 to de-repress SRBEP 17 , 18 . Thus, gp78 activity has detrimental effects on lipid biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11β-HSD1

Hu¹,

Han²,

Pan³

et al. 2022

Int. J. Biol. Sci.

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Glucocorticoids are essential participants in the regulation of lipid metabolism. On a tissue-specific level, glucocorticoid signal is controlled by 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1). Up-regulation of 11β-HSD1 expression during non-alcoholic fatty liver disease (NAFLD) has been previously shown, while 11β-HSD1 inhibition has been shown to reduce hepatic lipids in NAFLD, but the underlying mechanisms remain unclear. Here, in this study, we created in vitro cell culture and in vivo transgenic hepatocyte-specific 11β-HSD1 mouse models of NAFLD to determine the regulatory mechanisms of 11β-HSD1 during lipid metabolism dysfunction. We found that 11β-HSD1 overexpression activated glucocorticoid receptors and promoted their nuclear translocation, and then stimulating gp78. The induction of gp78 sharply reduced expression of Insig2, but not Insig1, which led to up-regulation of lipogenesis regulatory proteins including SREBP1, FAS, SCD1, and ACC1. Our results suggested that overexpression of 11β-HSD1 induced lipid accumulation, at least partially through the GR/gp78/Insig2/SREBP1 pathway, which may serve as a potential diagnostic and therapeutic target for treatment of NAFLD.

show abstract

Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2

Cited by 15 publications

References 55 publications

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

Cholesterol and Hedgehog Signaling: Mutual Regulation and Beyond

The GR-gp78 Pathway is involved in Hepatic Lipid Accumulation Induced by Overexpression of 11β-HSD1

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