gp78: a Multifaceted Ubiquitin Ligase that Integrates a Unique Protein Degradation Pathway from the Endoplasmic Reticulum

Chen, Zhiliang; Du, Shao Jun; Fang, Shengyun

doi:10.2174/138920312802430590

Cited by 32 publications

(36 citation statements)

References 110 publications

(168 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMFR/gp78 is an E3 ubiquitin ligase and INSIG is an insulin signaling factor (Flury et al, 2005; Chen et al, 2012). Both are localized to the ER membrane and when activated function together to degrade HMG COA reductase, a cholesterol synthesis enzyme (Jo et al, 2011; Tsai et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

Varicella-zoster virus glycoprotein expression differentially induces the unfolded protein response in infected cells

Carpenter¹,

Grose²

2014

Front. Microbiol.

View full text Add to dashboard Cite

Varicella-zoster virus (VZV) is a human herpesvirus that spreads to children as varicella or chicken pox. The virus then establishes latency in the nervous system and re-emerges, typically decades later, as zoster or shingles. We have reported previously that VZV induces autophagy in infected cells as well as exhibiting evidence of the Unfolded Protein Response (UPR): XBP1 splicing, a greatly expanded Endoplasmic Reticulum (ER) and CHOP expression. Herein we report the results of a UPR specific PCR array that measures the levels of mRNA of 84 different components of the UPR in VZV infected cells as compared to tunicamycin treated cells as a positive control and uninfected, untreated cells as a negative control. Tunicamycin is a mixture of chemicals that inhibits N-linked glycosylation in the ER with resultant protein misfolding and the UPR. We found that VZV differentially induces the UPR when compared to tunicamycin treatment. For example, tunicamycin treatment moderately increased (8-fold) roughly half of the array elements while downregulating only three (one ERAD and two FOLD components). VZV infection on the other hand upregulated 33 components including a little described stress sensor CREB-H (64-fold) as well as ER membrane components INSIG and gp78, which modulate cholesterol synthesis while downregulating over 20 components mostly associated with ERAD and FOLD. We hypothesize that this expression pattern is associated with an expanding ER with downregulation of active degradation by ERAD and apoptosis as the cell attempts to handle abundant viral glycoprotein synthesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Varicella-zoster virus glycoprotein expression differentially induces the unfolded protein response in infected cells

Carpenter¹,

Grose²

2014

Front. Microbiol.

View full text Add to dashboard Cite

show abstract

“…This is so, even though gp78 was not tampered with and was therefore present at its normal functional levels. These findings reveal that "in vivo" CHIP may serve quite early to prime CYP3A ubiquitination in the ER and that after such initial CHIP-mediated CYP3A priming, gp78 may act as an E4 to extend the polyUb chains (43,46). However, the finding that gp78 can per se effectively ubiquitinate P450s (and its other substrates) in in vitro reconstituted systems suggests that it can function both as an E3 and an E4 in P450 ERAD/Ub-dependent proteasomal degradation (30,(37)(38)(39)(40).…”

Section: Complementary Rather Than Redundant Roles Of Ubc7-gp78mentioning

confidence: 86%

“…4) (38). Notably, given that UBC7-gp78 operate as oligomeric E2-E3 complexes (44,46,91,92), their functional interactions with each CYP3A4 surface may entail the concurrent action of two or more distinct E2-E3 heteromeric units.…”

Section: Cyp3a4 Molecular Interactions With the Chip Complexour Chemimentioning

confidence: 99%

“…Herein, we document that although each of these E2-E3 systems can function quite independently in vitro, when present concurrently as in vivo, their roles in CYP3A4 ubiquitination are complementary rather than redundant. CYPs 3A and CYP2E1 thus belong to a growing list of canonical physiological substrates of UBC7-gp78 and UbcH5a-CHIP-Hsc70-Hsp40 E2-E3-Ub ligases (42)(43)(44)(45)(46)(47)(48)(49)(50).…”

mentioning

confidence: 99%

“…However, although many UBC7-gp78 heterologous substrates have now been identified (42)(43)(44)(45)(46), to our knowledge little is known about the mechanisms of their molecular recognition as specific cellular targets of this E2-E3 complex. In this study, we specifically address this issue and describe our characterization of CYP3A4 intermolecular interactions with UbcH5a-CHIP-Hsc70-Hsp40 and UBC7-gp78 E2-E3-Ub-ligase complexes, using complementary approaches of chemical cross-linking coupled with peptide mapping and high performance liquid chromatographic mass spectrometric (HPLC-MS/MS) analyses along with site-directed mutagenesis of CYP3A4 and/or the E3-ligase gp78.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Human Liver Cytochrome P450 3A4 Ubiquitination

Wang

Kim

Trnka³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: CYP3A4, a major human liver drug-metabolizing enzyme, is degraded upon phosphorylation and ubiquitination. Results: CYP3A4 phosphorylation occurs within negatively charged surface clusters that are important for electrostatic interactions with positively charged patches of the ubiquitination enzymes. Conclusion: These phosphorylated clusters enhance CYP3A4 molecular recognition by the ubiquitination complexes. Significance: This is the first mechanistic example of UBC7-gp78 substrate recognition.

show abstract

Hepatic cytochrome P450 ubiquitination: Conformational phosphodegrons for E2/E3 recognition?

et al. 2014

View full text Add to dashboard Cite

Hepatic endoplasmic reticulum (ER) integral cytochromes P450 (P450s) are monooxygenases engaged in the biotransformation and elimination of endo- as well as xenobiotics. Of the human liver P450s, CYP3A4 is the major and most dominant catalyst, responsible for the biotransformation of over 50% of clinically prescribed drugs. CYP2E1 metabolizes smaller molecular weight compounds (EtOH), carcinogens, environmental toxins and endobiotics, and is justly implicated in various toxigenic/pathogenic mechanisms of human disease. Both P450s are notorious for their potential to generate pathogenic reactive oxygen species (ROS) during futile oxidative cycling and/or oxidative uncoupling. Such ROS not only oxidatively damage the P450 catalytic cage, but on their escape into the cytosol, also the P450 outer surface and any surrounding cell organelles. Given their ER-monotopic topology coupled with this high potential to acquire oxidative lesions in their cytosolic (C) domain, not surprisingly these P450 proteins exhibit shorter lifespans and are excellent prototype substrates of ER-associated degradation (“ERAD-C”) pathway. Indeed, we have shown that both CYP3A4 and CYP2E1 incur ERAD-C, during which they are first phosphorylated by protein kinases A and C, which greatly enhance/accelerate their ubiquitination by UBC7/gp78 and UbcH5a/CHIP/Hsp70/Hsp40 E2/E3 ubiquitin ligase complexes. Such P450 phosphorylation occurs on Ser/Thr residues within linear sequences as well as spatially clustered acidic (Asp/Glu) residues. We propose that such S/T phosphorylation within these clusters creates a negatively charged patch i.e. conformational phosphodegrons, for interaction with positively charged E2/E3 domains. Such P450 S/T phosphorylation we posit serves as a switch to turn on its ubiquitination and ERAD-C.

show abstract

gp78: a Multifaceted Ubiquitin Ligase that Integrates a Unique Protein Degradation Pathway from the Endoplasmic Reticulum

Cited by 32 publications

References 110 publications

Varicella-zoster virus glycoprotein expression differentially induces the unfolded protein response in infected cells

Varicella-zoster virus glycoprotein expression differentially induces the unfolded protein response in infected cells

Human Liver Cytochrome P450 3A4 Ubiquitination

Hepatic cytochrome P450 ubiquitination: Conformational phosphodegrons for E2/E3 recognition?

Contact Info

Product

Resources

About