Mechanism of protein quality control at the endoplasmic reticulum

内质网蛋白质质量控​​制机制

基本信息

项目摘要

The endoplasmic reticulum (ER) is the major site of protein biosynthesis in eukaryotes. Polypeptides entering the ER may frequently adopt aberrant conformations, resulting in aggregation-prone, misfolded proteins. Accumulation of misfolded proteins induces ER stress, which has been implicated in the pathogenesis of many human diseases. To preserve ER protein homeostasis, eukaryotes have evolved a conserved quality control pathway termed retro-translocation/dislocation or ER-associated degradation (ERAD), which eliminates misfolded proteins from the ER by exporting them into the cytosol. Polypeptides undergoing retro-translocation are disposed of by the cytosolic proteasome. The retro-translocation pathway is hijacked by certain viruses to destroy folded cellular proteins required for immune response, allowing the virus to evade host immune surveillance. For example, the Human Immunodeficiency Virus uses a protein named Vpu to target newly synthesized CD4 co-receptor for degradation, which promote viral infection. We previously identified a cytosolic enzyme called p97, which acts with two co-factors Ufd1 and Npl4 to move retrotranslocating substrates into the cytosol for degradation. We also used an affinity purification approach to identify two novel ER membrane proteins, Derlin-1 and VIMP, which associate with p97. VIMP functions as a receptor to recruit p97 to the ER membrane. The conserved multi-spanning membrane protein Derlin-1 plays a central role in retro-translocation. It appears to receive substrates from the ER lumen to promote their translocation via a yet-to-be defined membrane pore. We further identified an ubiquitin ligase-associated multiprotein complex comprising Bag6, Ubl4A, and Trc35, which chaperones retrotranslocated polypeptides en route to the proteasome to improve ERAD efficiency. In vitro, Bag6, the central component of the complex, contains a chaperone-like activity capable of maintaining an aggregation-prone substrate in an unfolded yet soluble state. The physiological importance of this holdase activity is underscored by observations that ERAD substrates accumulate in detergent insoluble aggregates in cells depleted of Bag6, or of Trc35, a cofactor that keeps Bag6 outside the nucleus for engagement in ERAD. Our results reveal an ubiquitin ligase-associated holdase that maintains polypeptide solubility to enhance protein quality control in mammalian cells. The Bag6 complex also participates in several other protein quality control processes, but how Bag6 effectively captures misfolded polypeptides in the complex cellular environment is unclear. We recently found a novel ERAD mediator named SGTA, which forms a chaperone cascade with Bag6 to help channel dislocated ERAD substrates that are otherwise prone to aggregation. We show that SGTA contains an unusual ubiquitin-like (UBL) binding motif that interacts specifically with a non-canonical UBL domain in Ubl4A via electrostatics. This interaction enhances substrate loading to Bag6 to prevent the formation of non-degradable protein aggregates, and thus improve the ERAD efficiency. The Bag6-Ubl4A-Trc35 complex is a multifunctional chaperone that regulates various cellular processes. Because the diverse functions of Bag6 are supported by its ubiquitous localization to the cytoplasm, the nucleus, and membranes of the endoplasmic reticulum (ER) in cells, we recently investigated how Bag6 is associated with the ER membrane. We found that in the ER-associated degradation (ERAD) pathways, Bag6 can interact with the CUE domain in the membrane-associated ubiquitin ligase gp78 via its ubiquitin-like (UBL) domain, but the relative low affinity of this interaction does not reconcile with the fact that a fraction of Bag6 is tightly bound to the membrane. Here, we demonstrate that the UBL domain of Bag6 is required for its interaction with the ER membrane despite the low affinity to gp78. We findthat in addition to gp78, the Bag6 UBL domain also binds a UBL-binding motif in UbxD8, an essential component of the gp78 ubiquitinating machinery. Importantly, Bag6 forms a large homo-oligomer, allowing the UBL domain to form multivalent interactions with the gp78-containing retrotranslocation complex. Both gp78 and UbxD8 contain motifs for recognition by p97, thus linking Bag6 to this core retrotranslocation machinery in the membrane. We propose that simultaneous association with multiple ERAD factors helps to anchor a fraction of Bag6 oligomer to the site of retrotranslocation to enhance ERAD efficiency. Our research also addressed a surprising paradox emerging from recent studies that ubiquitin ligases (E3s) and deubiquitinases (DUBs), enzymes with opposing activities, can both promote ERAD. We demonstrate that the ERAD E3 gp78 can ubiquitinate not only ERAD substrates, but also the machinery protein Ubl4A, a key component of the Bag6 chaperone complex. Remarkably, instead of targeting Ubl4A for degradation, polyubiquitination is associated with irreversible proteolytic processing and inactivation of Bag6. Importantly, we identify USP13 as a gp78-associated DUB that eliminates ubiquitin conjugates from Ubl4A to maintain the functionality of Bag6. Our study reveals an unexpected paradigm in which a DUB prevents undesired ubiquitination to sharpen substrate specificity for an associated ubiquitin ligase partner and to promote ER quality control. We recently show that ribosome stalling during protein translocation induces the attachment of UFM1, a ubiquitin-like modifier, to two conserved lysine residues near the COOH-terminus of the 60S ribosomal subunit RPL26 (uL24) at the ER. Strikingly, RPL26 UFMylation enables the degradation of stalled nascent chains, but unlike ERAD or previously established cytosolic ribosome-associated quality control (RQC), which uses proteasome to degrade their client proteins, ribosome UFMylation promotes the targeting of a translocation-arrested ER protein to lysosomes for degradation. RPL26 UFMylation is upregulated during erythroid differentiation to cope with increased secretory flow, and compromising UFMylation impairs protein secretion, and ultimately hemoglobin production. We propose that in metazoan, co-translational protein translocation (TAQC) into the ER is safeguarded by a UFMylation-dependent, translocation-associated protein quality control mechanism, which when impaired causes anemia in mice and abnormal neuronal development in humans. More recently, we used a genome-wide CRISPR/Cas9 screen to identify an uncharacterized membrane protein named SAYSD1 that facilitates TAQC. SAYSD1 associates with the Sec61 translocon and engages a stalled nascent chain-ribosome complex by directly recognizing both ribosome and UFM1, ensuring the export of stalled substrates via the TRAPP complex for lysosomal degradation. Like UFM1 deficiency, SAYSD1 depletion causes the build-up of translocation-stalled proteins at the ER, which triggers ER stress. Importantly, disrupting UFM1- and SAYSD1-dependent quality control in Drosophila leads to the accumulation of translocation-stalled collagen, defective collagen deposition, abnormal basement membranes, and reduced stress tolerance. Together, our data support a model that SAYSD1 acts as an ER-associated UFM1 sensor to collaborate with ribosome UFMylation at the site of translocon-jamming, safeguarding ER homeostasis during animal development.

项目成果

期刊论文数量(21)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Doa1 is a MAD adaptor for Cdc48.
  • DOI:
    10.1083/jcb.201603078
  • 发表时间:
    2016-04-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Zhang T;Ye Y
  • 通讯作者:
    Ye Y
Ever HRD a ubiquitin-gated channel?
HRD 曾经是泛素门控通道吗?
  • DOI:
    10.1038/cr.2016.92
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    44.1
  • 作者:
    Zhang,Ting;Ye,Yihong
  • 通讯作者:
    Ye,Yihong
Clearing Traffic Jams During Protein Translocation Across Membranes.
gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum.
  • DOI:
    10.1091/mbc.e15-06-0354
  • 发表时间:
    2015-12-01
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Zhang T;Xu Y;Liu Y;Ye Y
  • 通讯作者:
    Ye Y
A spiral path to unfolding.
一条螺旋式的道路展开。
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Yihong Ye其他文献

Yihong Ye的其他文献

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{{ truncateString('Yihong Ye', 18)}}的其他基金

Mechanism of protein quality control at the endoplasmic reticulum
内质网蛋白质质量控​​制机制
  • 批准号:
    10697736
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Regulation of TNFa signaling by the dual ubiquitin modifying enzyme A20
双泛素修饰酶 A20 对 TNFa 信号传导的调节
  • 批准号:
    7734089
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Mechanism of protein retro-translocation from the endoplasmic reticulum
内质网蛋白质逆转位机制
  • 批准号:
    8148157
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Regulation and function of deubiquitinating enzyme USP19
去泛素化酶USP19的调控和功能
  • 批准号:
    9356202
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Role of the p97 ATPase in endocytosis
p97 ATP 酶在内吞作用中的作用
  • 批准号:
    8553639
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Roles of protein misfolding in neurodegenerative diseases
蛋白质错误折叠在神经退行性疾病中的作用
  • 批准号:
    10697852
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Regulation of TNFa signaling by the dual ubiquitin modifying enzyme A20
双泛素修饰酶 A20 对 TNFa 信号传导的调节
  • 批准号:
    7967367
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Mechanism of protein retro-translocation from the endoplasmic reticulum
内质网蛋白质逆转位机制
  • 批准号:
    8741408
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Regulation of deubiquitinating enzymes
去泛素化酶的调节
  • 批准号:
    8939700
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:
Mechanism of protein retro-translocation from the endoplasmic reticulum
内质网蛋白质逆转位机制
  • 批准号:
    9148777
  • 财政年份:
  • 资助金额:
    $ 77.97万
  • 项目类别:

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