TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum

Hassink, Gerco; Kikkert, Marjolein; Voorden, Sjaak van; Lee, Shiow Ju; Spaapen, Robbert M.; Laar, Theo van; Coleman, Catherine S.; Bartee, Eric; Früh, Klaus; Chau, Vincent; Wiertz, Emmanuel J. H. J.

doi:10.1042/bj20041241

Cited by 153 publications

(149 citation statements)

References 60 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…1B and 7A). As reported previously (42), WT and C9A co-localized with calnexin, and overexpression resulted in localization throughout the ER network. The G885L and N890A mutants both co-localized with calnexin and had patterns indistinguishable from WT MARCH6 -3xFLAG.…”

Section: The Doa10 Cte Promotes Efficient Deg1supporting

confidence: 85%

“…Endogenous MARCH6 and Exogenous MARCH6 CTE Mutants Localize to the ER-The human ortholog of Doa10, MARCH6 (TEB4), is also believed to be an ERAD ubiquitin ligase, although localization of the endogenously expressed protein to the ER has not been directly demonstrated (42). Like Doa10, MARCH6 appears to have 14 transmembrane domains with the N-terminal RING domain and C-terminal tail protruding into the cytoplasm (11).…”

Section: The Doa10 Cte Promotes Efficient Deg1mentioning

confidence: 99%

“…The CTE Is Required for Autoregulation of MARCH6 Degradation-A common mechanism for E3 ligase regulation is through autoubiquitylation and degradation by the proteasome (49). MARCH6 is among the E3 ligases known to trigger its own turnover in a manner that requires its ubiquitin ligase activity (42). To investigate the conservation of MARCH6 CTE function in protein degradation, we compared the steady-state levels and degradation kinetics of MARCH6-G885L and MARCH6-N890A with the WT and catalytically inactive C9A RING mutant versions of the ligase.…”

Section: The Doa10 Cte Promotes Efficient Deg1mentioning

confidence: 99%

See 2 more Smart Citations

A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation

Zattas

Berk

Kreft

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Specific proteins are modified by ubiquitin at the endoplasmic reticulum (ER) and are degraded by the proteasome, a process referred to as ER-associated protein degradation. In Saccharomyces cerevisiae, two principal ER-associated protein degradation ubiquitin ligases (E3s) reside in the ER membrane, Doa10 and Hrd1. The membrane-embedded Doa10 functions in the degradation of substrates in the ER membrane, nuclear envelope, cytoplasm, and nucleoplasm. How most E3 ligases, including Doa10, recognize their protein substrates remains poorly understood. Here we describe a previously unappreciated but highly conserved C-terminal element (CTE) in Doa10; this cytosolically disposed 16-residue motif follows the final transmembrane helix. A conserved CTE asparagine residue is required for ubiquitylation and degradation of a subset of Doa10 substrates. Such selectivity suggests that the Doa10 CTE is involved in substrate discrimination and not general ligase function. Functional conservation of the CTE was investigated in the human ortholog of Doa10, MARCH6 (TEB4), by analyzing MARCH6 autoregulation of its own degradation. Mutation of the conserved Asn residue (N890A) in the MARCH6 CTE stabilized the normally short lived enzyme to the same degree as a catalytically inactivating mutation (C9A). We also report the localization of endogenous MARCH6 to the ER using epitope tagging of the genomic MARCH6 locus by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome editing. These localization and CTE analyses support the inference that MARCH6 and Doa10 are functionally similar. Moreover, our results with the yeast enzyme suggest that the CTE is involved in the recognition and/or ubiquitylation of specific protein substrates.Selective protein degradation in eukaryotic cells is largely carried out by the ubiquitin-proteasome system. Proteins identified for degradation by the ubiquitin-proteasome system are covalently modified with ubiquitin, a highly conserved 76-residue protein (1, 2). In most cases, ubiquitin is conjugated to the target protein via an amide linkage between its C-terminal glycine and ⑀-amino groups on substrate lysine residues. Ubiquitylation requires an enzyme cascade beginning with an E1 ubiquitin-activating enzyme, which adenylates the ubiquitin C-terminal carboxyl group and subsequently forms a high energy thioester bond with it. Ubiquitin is then transferred from the E1 active site cysteine to a cysteine in an E2 ubiquitinconjugating enzyme. Finally, an E3 ubiquitin ligase mediates ubiquitin transfer from the E2 to the target protein. E3s come in several mechanistically distinct classes, but the most abundant are the RING E3s. The RING domain is characterized by a set of Cys and His residues that coordinate a pair of zinc ions; the RING directly contacts the E2-ubiquitin thioester-linked complex and promotes ubiquitin transfer to a substrate (3). Polyubiquitin chains are formed when the C terminus of one donor ubiquitin is conjugated to one of seven lysine residues, or the ...

show abstract

Section: The Doa10 Cte Promotes Efficient Deg1supporting

confidence: 85%

Section: The Doa10 Cte Promotes Efficient Deg1mentioning

confidence: 99%

Section: The Doa10 Cte Promotes Efficient Deg1mentioning

confidence: 99%

See 1 more Smart Citation

A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation

Zattas

Berk

Kreft

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Analogies to yeast Hrd1p͞Der3p further break down, because there is no identifiable human Cue1p ortholog. More recently, a mammalian Doa10p ortholog, TEB4, has been identified that may play a role in MHC regulation (19,20).…”

mentioning

confidence: 99%

The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site

Chen

Mariano

Tsai

et al. 2006

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

193

224

View full text Add to dashboard Cite

Efficient targeting of proteins for degradation from the secretory pathway is essential to homeostasis. This occurs through endoplasmic reticulum (ER)-associated degradation (ERAD). In this study, we establish that a human ubiquitin ligase (E3), gp78, and a specific E2, Ube2g2, are both critically important for ERAD of multiple substrates. gp78 exhibits a complex domain structure that, in addition to the RING finger, includes a ubiquitin-binding Cue domain and a specific binding site for Ube2g2. Disruption of either of these domains abolishes gp78-mediated ubiquitylation and protein degradation, resulting in accumulation of substrates in their fully glycosylated forms in the ER. This suggests that gp78-mediated ubiquitylation is an early step in ERAD that precedes dislocation of substrates from the ER. The in vivo requirement for both an E2-binding site distinct from the RING finger and a ubiquitin-binding domain intrinsic to an E3 suggests a previously unappreciated level of complexity in ubiquitin ligase function. These results also provide proof of principle that interrupting a specific E2-E3 interaction can selectively inhibit ERAD.autocrine motility factor receptor ͉ ubiquitin protein ligase ͉ ubiquitin ͉ unfolded protein response ͉ MmUBC7

show abstract

“…In yeast, the Hrd1 and Doa10 E3 ubiquitin ligases are central components of the membrane-associated ERAD machinery [67,68]. In mammals, no less than 16 E3 ligases have been implicated in the ERAD pathway, including HRD1 [69], gp78 [70], and TEB4 [71,72]. Constituents of the HRD1 complex are similar to those in yeast and include the adaptor protein SEL1L (similar to Hrd3) [73], the rhomboid pseudoprotease Derlin-1 (a homolog of Der1) [74,75], the scaffold protein Herp (Usa1) [76,77] and other lumenal and cytosolic factors.…”

Section: Eradmentioning

confidence: 99%

Genesis of ER stress in Huntington’s Disease

Shenkman

Eiger

Lederkremer

2015

Endoplasmic Reticulum Stress in Diseases

View full text Add to dashboard Cite

Recent research has identified ER stress as a major mechanism implicated in cytotoxicity in many neurodegenerative diseases, among them Huntington’s disease. This genetic disorder is of late-onset, progressive and fatal, affecting cognition and movement. There is presently no cure nor any effective therapy for the disease. This review focuses on recent findings that shed light on the mechanisms of the advent and development of ER stress in Huntington’s disease and on its implications, highlighting possible therapeutic avenues that are being or could be explored.

show abstract

TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum

Cited by 153 publications

References 60 publications

A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation

A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation

The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site

Genesis of ER stress in Huntington’s Disease

Contact Info

Product

Resources

About