ISG15‐dependent Regulation

Haas, Arthur

doi:10.1002/9783527619320.ch5b

Cited by 4 publications

(4 citation statements)

References 159 publications

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“…8 UbcH8 is an ISG15-specific E2 conjugating enzyme that forms an obligate thiolester catalyzed by UbE1L. 9,10 Although several E3s have been identified as possible ISG15 E3 ligases, the major E3 for ISG15 appears to be HERC5. 11 However, the incomplete loss of the ISG15 conjugates in HERC5-ablated cells suggests that other ISG15 E3 ligases may contribute to the ISG15 conjugation in vivo .…”

Section: Introductionmentioning

confidence: 99%

ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells

Desai

Reed

Burks

et al. 2012

Exp Biol Med (Maywood)

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The interferon-stimulated gene 15 (ISG15) pathway is highly elevated in breast cancer; however, very little is known about how the ISG15 pathway contributes to breast tumorigenesis. In the current study, using the gene disruption approach, we demonstrate that both ISG15 and UbcH8 (ISG15-specific conjugating enzyme) disrupt F-actin architecture and formation of focal adhesions in ZR-75-1 breast cancer cells. In addition, ISG15 and UbcH8 promote breast cancer cell migration. We also demonstrate that ISG15 inhibits ubiquitin/26S proteasome-mediated turnover of proteins implicated in tumor cell motility, invasion and metastasis. Together, our results suggest that the aberrant activation of the ISG15 pathway confers a motile phenotype to breast cancer cells by disrupting cell architecture and stabilizing proteins involved in cell motility, invasion and metastasis. Because the cellular architecture is conserved and the ISG15 pathway is constitutively activated in tumor cells of different lineages, it is reasonable to assume that our observations in breast cancer must hold true for many other tumors.

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Section: Introductionmentioning

confidence: 99%

ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells

Desai

Reed

Burks

et al. 2012

Exp Biol Med (Maywood)

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“…ISG15 is synthesized from the ISG15 gene, and either remains in an intracellular free form, appended to proteins in cells (conjugated form), or secreted from cells (extracellular form) by an unknown mechanism. [104][105][106] ISG15 conjugates to intracellular targets through a multi-enzyme pathway parallel to that of ubiquitin and other Ubl proteins (reviewed in literature 104,[107][108][109] ). ISG15-specific enzymes E1 (UbE1L), E2 (UbcH8), and E3 (HERC5, EFP, and several others) are also IFN-stimulated proteins that conjugate intracellular free ISG15 to cellular proteins, a mechanism referred to as ISGylation.…”

Section: Isg15 a Potential Modulator Of Mitophagy In Neurodegeneratimentioning

confidence: 99%

“…ISG15-specific enzymes E1 (UbE1L), E2 (UbcH8), and E3 (HERC5, EFP, and several others) are also IFN-stimulated proteins that conjugate intracellular free ISG15 to cellular proteins, a mechanism referred to as ISGylation. 108,[110][111][112] The ISG15 pathway (free ISG15 and its conjugates) is minimally expressed in normal cells. 24,106,[113][114][115] However, the ISG15 pathway is elevated in pathogen-infected cells, [116][117][118] malignancies, 25,26 A-T, 26 and ALS 93 cells.…”

Section: Isg15 a Potential Modulator Of Mitophagy In Neurodegeneratimentioning

confidence: 99%

Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases

Desai

Juncker

Kim

2018

Exp Biol Med (Maywood)

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Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.

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“…The precise mode of action of ISG15 is not yet established. ISGylation is believed to counteract Ubiquitination by competing for the same Lys in substrates [26] . Studies with UbcH6 and UbcH13 showed that ISGylation of these E2s hampered their ability to form a thiolester intermediate with Ub [27] , [28] .…”

Section: Introductionmentioning

confidence: 99%

HyperISGylation of Old World Monkey ISG15 in Human Cells

et al. 2008

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BackgroundISG15 is an Ubiquitin-like protein, highly induced by Type I Interferons. Upon the cooperative activity of specific Ubiquitinating enzymes, ISG15 can be conjugated to its substrates. Increasing evidence points to a role for protein ISGylation in anti-viral and anti-tumoral defense.Principal FindingsWe identified ISG15 from Old World Monkeys (OWm) as a hyper-efficient protein modifier. Western blot analysis visualized more efficient conjugation of OWmISG15 relative to HuISG15 in human (Hu), monkey and mouse (Mo) cell-lines. Moreover, the substrates of OWmISG15 identified upon Tandem Affinity Purification followed by LC-MS/MS identification largely outnumbered these of HuISG15 itself. Several Ubiquitin-Conjugating enzymes were identified as novel ISGylated substrates. Introduction of a N89D mutation in HuISG15 improved its ISGylation capacity, and additional Q31K/T33A/D133N mutations yielded a HuISG15 variant with an ISGylation efficiency comparable to OWmISG15. Homology modeling and structural superposition situate N89 in the interaction interface with the Activating enzyme. Analysis of the UbE1L residues in this interface revealed a striking homology between OWmUbE1L and HuUbE1, the Activating enzyme of Ubiquitin. In line with this observation, we found efficient activation of AgmISG15, but not HuISG15 or MoISG15, by HuUbE1, thus providing a likely explanation for OWm hyperISGylation.ConclusionsThis study discloses the poor conjugation competence of HuISG15 compared to OWmISG15 and maps the critical determinants for efficient conjugation. HyperISGylation may greatly assist ISGylation studies and may enhance its function as positive regulator of Interferon-related immune responses or as anti-tumoral modulator.

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ISG15‐dependent Regulation

Cited by 4 publications

References 159 publications

ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells

ISG15 disrupts cytoskeletal architecture and promotes motility in human breast cancer cells

Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases

HyperISGylation of Old World Monkey ISG15 in Human Cells

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