Serine Residues in the Cytosolic Tail of the T-cell Antigen Receptor α-Chain Mediate Ubiquitination and Endoplasmic Reticulum-associated Degradation of the Unassembled Protein

Ishikura, Shuhei; Weissman, Allan M.; Bonifacino, Juan S.

doi:10.1074/jbc.m110.127936

Cited by 84 publications

(93 citation statements)

References 52 publications

(78 reference statements)

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“…ERAD substrates are ubiquitinated at serine/threonine residues and less frequently at lysine residues (Shimizu et al 2010). This process is apparently different from that of other cytosolic ubiquitination mechanisms Ishikura et al 2010). At the cytosolic face of the ERAD complex, the AAAþ ATPase p97/VCP (Cdc48 in yeast) hexamer directs substrate to be drawn into the cytosol .…”

Section: Retrotranslocation and Degradationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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Section: Retrotranslocation and Degradationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

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“…Although the ubiquitination and HRD1/UBE2J1-mediated dislocation of a lysineless MHC I HC was unexpected, it was not without precedent. Other HRD1 substrates, TCRα (18) and NS-1 Ig light chain (19), can be ubiquitinated on serine/threonine residues, although the requisite E2 enzymes were not identified. Intriguingly, murine UBE2J2, the closest homolog of UBE2J1, cooperates with murine γ-herpesvirus K3 ligase to ubiquitinate serine and lysine residues on murine MHC I HCs (20).…”

Section: Discussionmentioning

confidence: 99%

“…The only integral membrane protein targeted by the cellular ERAD machinery for which sites of ubiquitination are defined is TCRα, a type I transmembrane glycoprotein targeted by both HRD1 and gp78, and ubiquitinated on its cytosolic tail (18,27). In contrast to MHC I HC, in which the folding defect (degron) appears to be located within the luminal domain, unpaired charged residues in the transmembrane domain of TCRα are essential for ERAD (28), suggesting that location of the degron may be important for determining the site of ubiquitination and ligase involved.…”

Section: Discussionmentioning

confidence: 99%

MHC class I molecules are preferentially ubiquitinated on endoplasmic reticulum luminal residues during HRD1 ubiquitin E3 ligase-mediated dislocation

Burr

Boomen

Bye

et al. 2013

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

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Misfolded MHC class I heavy chains (MHC I HCs) are targeted for endoplasmic reticulum (ER)-associated degradation (ERAD) by the ubiquitin E3 ligase HRD1, and E2 ubiquitin conjugating enzyme UBE2J1, and represent one of the few known endogenous ERAD substrates. The mechanism by which misfolded proteins are dislocated across the ER membrane into the cytosol is unclear. Here, we investigate the requirements for MHC I ubiquitination and degradation and show that endogenous misfolded MHC I HCs are recognized in the ER lumen by EDEM1 in a glycan-dependent manner and targeted to the core SEL1L/HRD1/UBE2J1 complex. A soluble MHC I HC lacking its transmembrane domain and cytosolic tail uses the same ERAD components and is degraded as efficiently as wildtype MHC I. Unexpectedly, HRD1-dependent polyubiquitination is preferentially targeted to the ER luminal domain of full-length MHC I HCs, despite the presence of an exposed cytosolic C-terminal tail. MHC I luminal domain ubiquitination occurs before p97 ATPase-mediated extraction from the ER membrane and can be targeted to nonlysine, as well as lysine, residues. A subset of integral membrane proteins, therefore, requires an early dislocation event to expose part of their luminal domain to the cytosol, before HRD1-mediated polyubiquitination and dislocation.T he assembly and regulated expression of plasma membrane and secreted proteins is fundamentally reliant on effective endoplasmic reticulum quality control (ERQC). Endoplasmic reticulum (ER)-associated degradation (ERAD) is central to ERQC, selectively disposing of misfolded or surplus proteins to maintain ER homeostasis. ERAD involves recognition, ubiquitination, and retrotranslocation of substrates from the ER to the cytosol for proteasome-mediated degradation (1). Polyubiquitination of the substrate is critical, both for facilitating ER membrane extraction by the p97 ATPase-ubiquitin fusion degradation 1 (Ufd1)-nuclear protein localization 4 (Npl4) complex (2-4) and for delivery to the proteasome. However, the precise role of ubiquitin in the actual dislocation event is unclear.The cellular ERAD machinery consists of multiprotein complexes, typically comprising a membrane-embedded ubiquitin E3 ligase, which engages substrates directly or via ER luminal adaptors (1). Different substrates degraded by the same E3 may use distinct ERAD cofactors that facilitate substrate delivery to the ligase and E2-conjugating enzyme for ubiquitination.Attempts to delineate distinct degradation pathways according to the site of the defect in a misfolded protein have been made in yeast. Proteins with cytosolic defects (ERAD-C) require Doa10p, whereas proteins with transmembrane (ERAD-M) or luminal (ERAD-L) lesions use Hrd1p (5, 6). The expanded repertoire of ERAD E3s in mammalian cells makes developing analogous rules more challenging. 3-hydroxy-3-methylglutaryl-CoA reductase degradation protein 1 (HRD1) and its homolog gp78/autocrine motility factor receptor (AMFR) are the best-characterized mammalian ERAD ligases. The association of HR...

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“…Ubiquitination of the N-terminal amino group was first observed on metazoan myogenic differentiation1 (MyoD; Breitschopf et al, 1998) and subsequently observed on other proteins (for review, see Ciechanover and Ben-Saadon, 2004). Non-Lys ubiquitination was first described on mammalian major histocompatibility complex class I a-chain (Cadwell and Coscoy, 2005) and has been subsequently found on other proteins from metazoans and yeast (Wang et al, 2007(Wang et al, , 2012Ishikura et al, 2010;Shimizu et al, 2010;Domingues and Ryoo, 2012;Kravtsova-Ivantsiv and Ciechanover, 2012;Boban et al, 2015). Such alternativesite ubiquitination involves Ser and/or Thr hydroxyl groups as oxyesters and Cys sulfhydryl groups as thioesters (for review, see Kravtsova-Ivantsiv and Ciechanover, 2012).…”

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confidence: 99%

Lysine Residues Are Not Required for Proteasome-Mediated Proteolysis of the Auxin/Indole Acidic Acid Protein IAA1

Gilkerson

Kelley²,

Tam

et al. 2015

Plant Physiol.

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Although many ubiquitin-proteasome substrates have been characterized in plants, very little is known about the corresponding ubiquitin attachment(s) underlying regulated proteolysis. Current dogma asserts that ubiquitin is typically covalently attached to a substrate through an isopeptide bond between the ubiquitin carboxy terminus and a substrate lysyl amino group. However, nonlysine (non-Lys) ubiquitin attachment has been observed in other eukaryotes, including the N terminus, cysteine, and serine/threonine modification. Here, we investigate site(s) of ubiquitin attachment on indole-3-acetic acid1 (IAA1), a short-lived Arabidopsis (Arabidopsis thaliana) Auxin/indole-3-acetic acid (Aux/IAA) family member. Most Aux/IAA proteins function as negative regulators of auxin responses and are targeted for degradation after ubiquitination by the ubiquitin ligase SCF TIR1/AFB (for S-Phase Kinase-Associated Protein1, Cullin, F-box [SCF] with Transport Inhibitor Response1 [TIR1]/Auxin Signaling F-box [AFB]) by an interaction directly facilitated by auxin. Surprisingly, using a Histidine-Hemaglutinin (HIS 6x -HA 3x ) epitope-tagged version expressed in vivo, Lys-less IAA1 was ubiquitinated and rapidly degraded in vivo. Lys-substituted versions of IAA1 localized to the nucleus as Yellow Fluorescent Protein fusions and interacted with both TIR1 and IAA7 in yeast (Saccharomyces cerevisiae) two-hybrid experiments, indicating that these proteins were functional. Ubiquitination on both HIS 6x -HA 3x -IAA1 and Lys-less HIS 6x -HA 3x -IAA1 proteins was sensitive to sodium hydroxide treatment, indicative of ubiquitin oxyester formation on serine or threonine residues. Additionally, baseresistant forms of ubiquitinated IAA1 were observed for HIS 6x -HA 3x -IAA1, suggesting additional lysyl-linked ubiquitin on this protein. Characterization of other Aux/IAA proteins showed that they have diverse degradation rates, adding additional complexity to auxin signaling. Altogether, these data indicate that Aux/IAA family members have protein-specific degradation rates and that ubiquitination of Aux/IAAs can occur on multiple types of amino residues to promote rapid auxin-mediated degradation.The ubiquitin-proteasome system (UPS) is the major pathway for degradation of regulatory proteins in eukaryotic cells. Ubiquitin (UBQ), an approximately 8-kD protein, is covalently ligated to substrates, often with additional UBQs linked to each other to form a polyubiquitin chain. UBQ chains with specific UBQ-UBQ linkages facilitate interaction between substrates and the 26S proteasome, a multifunctional protease. Ligation of UBQ to substrates requires three enzymatic activities in series: E1 UBQ-activating enzyme, E2 UBQ-conjugating enzyme, and an E3 ubiquitin ligase. UBQ attachment begins with the ATP-dependent covalent linkage of UBQ through its carboxy terminus to the E1 active-site Cys. The E1 then transfers thioester-linked activated UBQ to the E2 active-site Cys, forming a UBQ-charged E2. The UBQ-charged E2 interacts with an E3. E3 ligases bind ...

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Serine Residues in the Cytosolic Tail of the T-cell Antigen Receptor α-Chain Mediate Ubiquitination and Endoplasmic Reticulum-associated Degradation of the Unassembled Protein

Cited by 84 publications

References 52 publications

Protein Folding and Quality Control in the ER

Protein Folding and Quality Control in the ER

MHC class I molecules are preferentially ubiquitinated on endoplasmic reticulum luminal residues during HRD1 ubiquitin E3 ligase-mediated dislocation

Lysine Residues Are Not Required for Proteasome-Mediated Proteolysis of the Auxin/Indole Acidic Acid Protein IAA1

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