Maintenance of organellar protein homeostasis by ER-associated degradation and related mechanisms

Lemberg, Marius K.; Střı́šovský, Kvido

doi:10.1016/j.molcel.2021.05.004

Cited by 89 publications

(63 citation statements)

References 123 publications

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“…The N-terminal region of ATF6 functions as a transcription factor and stimulates expression of target genes, such as protein disulfide isomerase (PDI), XBP1, and C/EBP Homologous Protein (CHOP) [16,17]. When proteins cannot be repaired or folded back into their functional configurations, they are targeted for degradation by ERAD [18]. When the repair capacity of ERAD is crossed, portions of the ER can be specifically targeted for degradation through autophagy (ER-phagy) [19].…”

Section: Introductionmentioning

confidence: 99%

Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

Paul

2021

Antioxidants

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Huntington’s disease (HD) is caused by expansion of polyglutamine repeats in the protein huntingtin, which affects the corpus striatum of the brain. The polyglutamine repeats in mutant huntingtin cause its aggregation and elicit toxicity by affecting several cellular processes, which include dysregulated organellar stress responses. The Golgi apparatus not only plays key roles in the transport, processing, and targeting of proteins, but also functions as a sensor of stress, signaling through the Golgi stress response. Unlike the endoplasmic reticulum (ER) stress response, the Golgi stress response is relatively unexplored. This review focuses on the molecular mechanisms underlying the Golgi stress response and its intersection with cysteine metabolism in HD.

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Section: Introductionmentioning

confidence: 99%

Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

Paul

2021

Antioxidants

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“…NRF3 is regulated by ER retention and endoplasmic-reticulum-associated degradation (ERAD), two cellular mechanisms responsible for surveillance of protein folding [7,8]. ERAD is a multi-step process in which misfolded proteins are recognized, retrotranslocated into the cytoplasm and targeted for degradation by the proteasome [8][9][10][11]. Recognition of misfolded proteins involves lectins and chaperone proteins in the ER [8].…”

Section: Introductionmentioning

confidence: 99%

Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

et al. 2021

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Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumor of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.

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“…ERAD plays a critical role in proteostasis under normal or stress conditions. Proteins that fail to fold or assemble are recognized by chaperones and lectins, transferred to membrane-integral adaptors and retrotranslocated through E3 ubiquitin ligases, followed by ubiquitination for cytosolic proteasomal degradation [27][28][29][30] . The ERAD system consists of several parallel pathways, ERAD-L, ERAD-M, and ERAD-C, handling the substrate proteins in the ER lumen, ER membrane, and ER cytoplasmic surface, respectively 28,31−34 .…”

Section: Introductionmentioning

confidence: 99%

Precursors of select GPI-anchored proteins positively regulate GPI biosynthesis under the control of ERAD

Liu¹,

Wang²,

Zhou³

et al. 2021

Preprint

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We previously reported that glycosylphosphatidylinositol (GPI) biosynthesis is regulated by endoplasmic reticulum associated degradation (ERAD); however, the underlying mechanistic basis remains unclear. Based on a genome-wide CRISPR–Cas9 screen, we show that a widely expressed GPI-anchored protein CD55 precursor and ER-resident ARV1 together upregulate GPI biosynthesis under ERAD-deficient conditions. In cells defective in GPI transamidase, GPI-anchored protein precursors fail to obtain GPI, remaining the uncleaved GPI-attachment signal at the C-termini. We show that ERAD deficiency causes accumulation of the CD55 precursor, which in turn upregulates GPI biosynthesis, where the GPI-attachment signal peptide is the active element. Among the 32 GPI-anchored proteins tested, only the GPI-attachment signal peptides of CD55 and CD48 enhance GPI biosynthesis. ARV1 is essential for the GPI upregulation by CD55 precursor. Our data demonstrate an ARV1-dependent regulatory connection between GPI biosynthesis and precursors of select GPI-anchored proteins that are under the control of ERAD.

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Maintenance of organellar protein homeostasis by ER-associated degradation and related mechanisms

Cited by 89 publications

References 123 publications

Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

Precursors of select GPI-anchored proteins positively regulate GPI biosynthesis under the control of ERAD

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