The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation

Tsai, Ya Chea; Mendoza, Arnulfo; Mariano, Jennifer; Zhou, Ming; Kostova, Zlatka; Chen, Bin; Veenstra, Timothy D.; Hewitt, Stephen M.; Helman, Lee J.; Khanna, Chand; Weissman, Allan M.

doi:10.1038/nm1686

Cited by 178 publications

(192 citation statements)

References 25 publications

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“…Hrd1 and gp78 serve divergent ERAD substrate populations (20,24,36,37). gp78 differs from Hrd1 in its complex domain structure, which, in addition to its RING finger, includes the ubiquitin-binding Cue domain (23, 24, 36).…”

Section: Discussionmentioning

confidence: 99%

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

Ying

Wang

Fan

et al. 2011

Journal of Biological Chemistry

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Familial encephalopathy with neuroserpin inclusion bodies is a neurodegenerative disorder characterized by the accumulation of neuroserpin polymers in the endoplasmic reticulum (ER) of cortical and subcortical neurons in the CNS because of neuroserpin point mutations. ER-associated degradation (ERAD) is involved in mutant neuroserpin degradation. In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. Overexpression of Hrd1 and gp78 decreases the mutant neuroserpin protein level, whereas Hrd1 and gp78 knockdown increases mutant neuroserpin stability. Moreover, ERAD impairment by mutant valosin-containing protein increases the mutant neuroserpin protein level and aggregate formation. Thus, these findings identify mutant neuroserpin as an ERAD target and show that Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway.Misfolding of specific proteins can lead to the formation of aggregates, which is associated with most neurodegenerative disorders. Protein aggregates are extracellular in Alzheimer's disease, cytosolic in Parkinson's disease and amyotrophic lateral sclerosis, both cytosolic and intranuclear in polyglutamine (polyQ) 3 diseases, and localize to the endoplasmic reticulum (ER) in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is caused by neuroserpin mutations (1). Although the role of the protein aggregates in the pathogenesis of these diseases is still poorly understood, a common feature of these aggregates is that they are all marked by ubiquitin. Neurodegenerative protein aggregation is closely related to the ubiquitin-proteasome system, a major cellular turnover system (2). Mutant neuroserpin aggregates have been observed in brain and cultured cells (3, 4). Neuroserpin is a secretory glycoprotein (5) that is a member of the serine protease inhibitor serpin family, and it is mainly expressed in the CNS (6). Mutations in neuroserpin result in its misfolding and accumulation in the ER (3, 4, 7). To date, four mutants of neuroserpin, S49P, S52R, H338R, and G392E, have been identified in association with FENIB (8). In FENIB-diseased brains, G392E, the most disruptive mutant, forms more inclusion bodies and at an earlier age of onset (13 years) than the other neuroserpin mutants (9). Because the earlier onset of FENIB is strongly correlated with the level of intracellular neuroserpin accumulation, neuroserpin accumulation appears to play a central role in FENIB pathology.Many accumulated proteins that are caused by mutations or ER stress are targeted by a protein quality control system, termed ER-associated degradation (ERAD). ERAD is a degradation system in which proteins that are misfolded in the ER are exported to the cytosol for proteasomal degradation (10, 11). ER-associated E3 ubiquitin ligases, together with the VCPUfd1-Npl4 complex, are key components of the ERAD machinery. During the ERAD process, selected proteins are ubiquitinated by E3 ubiquitin lig...

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Section: Discussionmentioning

confidence: 99%

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

Ying

Wang

Fan

et al. 2011

Journal of Biological Chemistry

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“…To study Gp78-mediated regulation of ER-mitochondria interaction by electron microscopy, we stably transfected HT-1080 fibrosarcoma cells, which express elevated levels of endogenous Gp78 (St-Pierre et al, 2012;Tsai et al, 2007), with doxycyclininducible Gp78 short hairpin RNA (shRNA; shGp78). 3D confocal analysis showed that shGp78 knockdown reduced syntaxin-17 overlap with mitochondria ( Fig.…”

Section: Amf-gp78 Selectively Regulate Rer-mitochondria Contactsmentioning

confidence: 99%

Distinct mechanisms controlling rough and smooth endoplasmic reticulum-mitochondria contacts

Wang

Garcin

et al. 2015

Journal of Cell Science

102

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Gp78 (also known as AMFR), an endoplasmic-reticulum (ER)-associated protein degradation (ERAD) E3 ubiquitin ligase, localizes to mitochondria-associated ER and targets the mitofusin (Mfn1 and Mfn2) mitochondrial fusion proteins for degradation. Gp78 is also the cell surface receptor for autocrine motility factor (AMF), which prevents Gp78-dependent mitofusin degradation. Gp78 ubiquitin ligase activity promotes ER-mitochondria association and ER-mitochondria Ca 2+ coupling, processes that are reversed by AMF. Electron microscopy of HT-1080 fibrosarcoma cancer cells identified both smooth ER (SER; ∼8 nm) and wider (∼50-60 nm) rough ER (RER)-mitochondria contacts. Both short hairpin RNA (shRNA)-mediated knockdown of Gp78 (shGp78) and AMF treatment selectively reduced the extent of RER-mitochondria contacts without impacting on SER-mitochondria contacts. Concomitant small interfering RNA (siRNA)-mediated knockdown of Mfn1 increased SER-mitochondria contacts in both control and shGp78 cells, whereas knockdown of Mfn2 increased RER-mitochondria contacts selectively in shGp78 HT-1080 cells. The mitofusins therefore inhibit ER-mitochondria interaction. Regulation of close SER-mitochondria contacts by Mfn1 and of RER-mitochondria contacts by AMFsensitive Gp78-mediated degradation of Mfn2 define new mechanisms that regulate ER-mitochondria interactions.

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“…This suggests that AMFR primarily functions to maintain the solubility of retrotranslocated polypeptides (42). Furthermore, SYVN1 is essential for ubiquitination of both luminal and membrane ERAD substrates, whereas AMFR does not share a similar role in retrotranslocation as transmembrane domains of AMFR are dispensable for ERAD (40,43). These studies and others point to an increasingly important role for SYVN1 in ERAD and possibly an essential role in ⌬F508-CFTR degradation.…”

Section: Distinct Complexes Degrade ⌬F508-cftr December 2 2016 • Volmentioning

confidence: 92%

SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation

Ramachandran

Osterhaus

Parekh

et al. 2016

Journal of Biological Chemistry

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Edited by George DeMartinoWe previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (⌬F508/⌬F508) airway epithelia partially restored ⌬F508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl ؊ conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ⌬F508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ⌬F508-CFTR-mediated Cl ؊ transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ⌬F508-CFTR-mediated Cl ؊ conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ⌬F508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ⌬F508-CFTR ubiquitination.

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The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation

Cited by 178 publications

References 25 publications

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

Distinct mechanisms controlling rough and smooth endoplasmic reticulum-mitochondria contacts

SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation

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