A Principal Role for the Proteasome in Endoplasmic Reticulum-associated Degradation of Misfolded Intracellular Cystic Fibrosis Transmembrane Conductance Regulator

Gelman, Marina S.; Kannegaard, Elisa Sandoval; Kopito, Ron R.

doi:10.1074/jbc.m111958200

Cited by 124 publications

(103 citation statements)

References 33 publications

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“…2 These data indicate that L166P would produce insufficient protein as a result of proteasomal degradation. This situation is similar to that seen with mutant forms of other recessive gene products such as the cystic fibrosis transmembrane receptor (28) or the neurofibromatosis type 2 gene product, schwannomin (29). The ubiquitin-proteasome system also degrades some dominant negative mutations such as caveolin-3 mutations associated with limb-girdle muscular dystrophy type 1C (30).…”

Section: Discussionmentioning

confidence: 56%

L166P Mutant DJ-1, Causative for Recessive Parkinson's Disease, Is Degraded through the Ubiquitin-Proteasome System

Miller

Ahmad

Hague

et al. 2003

Journal of Biological Chemistry

218

181

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Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, earlyonset Parkinson's disease. While one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point mutation, L166P, whose precise effects on protein function are unclear. In the present study, we show that L166P destabilizes DJ-1 protein and promotes its degradation through the ubiquitin-proteasome system. A double mutant (K130R, L166P) was more stable than L166P, suggesting that this lysine residue contributes to stability of the protein. Subcellular localization was broadly similar for both wild type and L166P forms of the protein, indicating that the effect of the mutation is predominantly on protein stability. These observations are reminiscent of other recessive gene mutations that produce an effective loss of function. The L166P mutation has the simple effect of promoting DJ-1 degradation, thereby reducing net DJ-1 protein within the cell.

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Section: Discussionmentioning

confidence: 56%

L166P Mutant DJ-1, Causative for Recessive Parkinson's Disease, Is Degraded through the Ubiquitin-Proteasome System

Miller

Ahmad

Hague

et al. 2003

Journal of Biological Chemistry

218

181

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“…Proteasome-mediated degradation has been demonstrated to play a critical role in CFTR turnover (45). As expected, proteasome inhibition during the pulse-labeling phase resulted in an increased yield of CFTR; however, the magnitude of the increase in CFTR supports a biphasic degradative mechanism including a co-translational phase (Fig.…”

Section: Uch-l1 Alters the Proteasomal Degradation Of Cftr Duringmentioning

confidence: 53%

Ubiquitin C-terminal Hydrolase-L1 Protects Cystic Fibrosis Transmembrane Conductance Regulator from Early Stages of Proteasomal Degradation

Henderson¹,

Vij²,

Zeitlin³

2010

Journal of Biological Chemistry

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⌬F508 cystic fibrosis transmembrane conductance regulator (CFTR) degradation involves ubiquitin modification and efficient proteasomal targeting of the nascent misfolded protein.We show that a deubiquitinating enzyme, ubiquitin C-terminal hydrolase-L1 (UCH-L1), is highly expressed in cystic fibrosis (CF) airway epithelial cells in vitro and in vivo. We hypothesized that the elevation in UCH-L1 in CF cells represents a cellular adaptation to counterbalance excessive proteasomal degradation. The bronchial epithelial cell lines IB3-1 (CF, high UCH-L1 expression) and S9 (non-CF, low UCH-L1 expression) were transiently transfected with wild type (WT) or ⌬F508 CFTR, WT UCH-L1 or small interfering RNA-UCH-L1, and a variety of ubiquitin mutants. We observed a positive correlation between UCH-L1 expression and steady state levels of WT-or ⌬F508-CFTR, and this stabilizing effect was confined to the early stages of CFTR synthesis. Immunolocalization of UCH-L1 by confocal microscopy revealed a partial co-localization with a ribosomal subunit and the endoplasmic reticulum. The UCH-L1-associated increase in CFTR levels was correlated with an increase in ubiquitinated CFTR (CFTR-Ub). Co-transfection with mutant ubiquitins and treatment with proteasome inhibitors suggested that UCH-L1 was reducing the proteasomal targeting of CFTR during synthesis by shortening conjugated polyubiquitin chains. Although not sufficient by itself to rescue mutant CFTR therapeutically, the elevation of UCH-L1 and its effect on CFTR processing provides insight into its potential roles in CF and other diseases.

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“…Interestingly, the two proteasome inhibitors also increased the expression of YFP-M1. Epoxomicin is more specific than MG132, which can also inhibit lysosomal calpains and cysteine proteases (41,42). The augmentation of YFP-M1 expression following epoxomicin treatment shows a role of the proteasome in the turnover of MARCH1, in line with the presence of K48-linked polyubiquitin chains (Fig.…”

Section: Ubiquitination Of March1 Regulates Its Turnovermentioning

confidence: 82%

Autoregulation of MARCH1 Expression by Dimerization and Autoubiquitination

Bourgeois-Daigneault

Thibodeau

2012

The Journal of Immunology

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Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain-specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination.

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A Principal Role for the Proteasome in Endoplasmic Reticulum-associated Degradation of Misfolded Intracellular Cystic Fibrosis Transmembrane Conductance Regulator

Cited by 124 publications

References 33 publications

L166P Mutant DJ-1, Causative for Recessive Parkinson's Disease, Is Degraded through the Ubiquitin-Proteasome System

L166P Mutant DJ-1, Causative for Recessive Parkinson's Disease, Is Degraded through the Ubiquitin-Proteasome System

Ubiquitin C-terminal Hydrolase-L1 Protects Cystic Fibrosis Transmembrane Conductance Regulator from Early Stages of Proteasomal Degradation

Autoregulation of MARCH1 Expression by Dimerization and Autoubiquitination

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