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Dr. Dorianna Sandonà

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Guest Editor

Department of Biomedical Sciences, University of Padova, Italy
Interests: sarcoglycanopathies; muscular dystrophy; rare diseases; striated muscle; folding defective proteins; ERAD; small molecules; pharmacological therapy

Dr. Marcello Carotti

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Guest Editor

Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: sarcoglycanopathies; folding defective proteins; ERAD; protein(bio)synthesis; enzymology; zebrafish; genome editing

Special Issue Information

The endoplasmic reticulum (ER) is the site where about one-third of the eukaryotic proteome undergoes maturation and is monitored for proper folding. Protein homeostasis in the ER is assured by multiple quality control (QC) checkpoints that triage each newly synthetized protein, allowing the native ones to proceed toward the final destination and delivering the defective ones to either ER-associated degradation (ERAD), ER-phagy, the Golgi-QC, or the plasma membrane-QC. When ERQC fails, stress response pathways such as the unfolded protein response (UPR) are induced.

The present Special Issue of IJMS will mainly focus on the role of ERAD in the physiological and pathological status of cells and tissues. Indeed, ERAD directly or indirectly influences metabolism and immunity, and regulates specific enzyme concentrations as well as the stoichiometry of oligomeric complexes. ERAD targets proteins with inefficient folding and is responsible for the disposal of most of the misfolded proteins arising from genetic mutations, biosynthesis mistakes, or compound toxicity. More than 70 human diseases are associated with ERAD, and growing evidence highlights the involvement of this pathway in cancer. Thus, studying the ERAD pathways in different tissues could unveil the molecular mechanism(s) of such diseases, envisaging novel and specific pharmacological interventions modulating ERAD to avoid/improve degradation or correct the protein architecture.

Dr. Dorianna Sandonà
Dr. Marcello Carotti
Guest Editors

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Keywords

endoplasmic-reticulum-associated degradation (ERAD)
protein folding
folding-defective proteins
protein quality control
cell metabolism
immunity
cancer
conformational diseases
pharmacological intervention
protein correctors

Published Papers (2 papers)

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Research

14 pages, 2574 KiB

Open AccessArticle

Comparative Analysis of CREB3 and CREB3L2 Protein Expression in HEK293 Cells

by Kentaro Oh-hashi, Ayumi Yamamoto, Ryoichi Murase and Yoko Hirata

Int. J. Mol. Sci. 2021, 22(5), 2767; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052767 - 09 Mar 2021

Cited by 4 | Viewed by 2691

Abstract

We performed a comparative analysis of two ER-resident CREB3 family proteins, CREB3 and CREB3L2, in HEK293 cells using pharmacological and genome editing approaches and identified several differences between the two. Treatment with brefeldin A (BFA) and monensin induced the cleavage of full-length CREB3 and CREB3L2; however, the level of the full-length CREB3 protein, but not CREB3L2 protein, was not noticeably reduced by the monensin treatment. On the other hand, treatment with tunicamycin (Tm) shifted the molecular weight of the full-length CREB3L2 protein downward but abolished CREB3 protein expression. Thapsigargin (Tg) significantly increased the expression of only full-length CREB3L2 protein concomitant with a slight increase in the level of its cleaved form. Treatment with cycloheximide and MG132 revealed that both endogenous CREB3 and CREB3L2 are proteasome substrates. In addition, kifunensine, an α-mannosidase inhibitor, significantly increased the levels of both full-length forms. Consistent with these findings, cells lacking SEL1L, a crucial ER-associated protein degradation (ERAD) component, showed increased expression of both full-length CREB3 and CREB3L2; however, cycloheximide treatment downregulated full-length CREB3L2 protein expression more rapidly in SEL1L-deficient cells than the full-length CREB3 protein. Finally, we investigated the induction of the expression of several CREB3 and CREB3L2 target genes by Tg and BFA treatments and SEL1L deficiency. In conclusion, this study suggests that both endogenous full-length CREB3 and CREB3L2 are substrates for ER-associated protein degradation but are partially regulated by distinct mechanisms, each of which contributes to unique cellular responses that are distinct from canonical ER signals. Full article

(This article belongs to the Special Issue Physio-Pathological Role of ERAD and Its Pharmacological Modulation)

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25 pages, 4365 KiB

Open AccessArticle

EDEM3 Domains Cooperate to Perform Its Overall Cell Functioning

by Georgiana Manica, Simona Ghenea, Cristian V. A. Munteanu, Eliza C. Martin, Cristian Butnaru, Marius Surleac, Gabriela N. Chiritoiu, Petruta R. Alexandru, Andrei-Jose Petrescu and Stefana M. Petrescu

Int. J. Mol. Sci. 2021, 22(4), 2172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042172 - 22 Feb 2021

Cited by 6 | Viewed by 2968

Abstract

EDEM3 recognizes and directs misfolded proteins to the ER-associated protein degradation (ERAD) process. EDEM3 was predicted to act as lectin or as a mannosidase because of its homology with the GH47 catalytic domain of the Man1B1, but the contribution of the other regions remained unresolved. Here, we dissect the molecular determinants governing EDEM3 function and its cellular interactions. LC/MS analysis indicates very few stable ER interactors, suggesting EDEM3 availability for transient substrate interactions. Sequence analysis reveals that EDEM3 consists of four consecutive modules defined as GH47, intermediate (IMD), protease-associated (PA), and intrinsically disordered (IDD) domain. Using an EDEM3 knock-out cell line, we expressed EDEM3 and domain deletion mutants to address EDEM3 function. We find that the mannosidase domain provides substrate binding even in the absence of mannose trimming and requires the IMD domain for folding. The PA and IDD domains deletions do not impair the trimming, but specifically modulate the turnover of two misfolded proteins, NHK and the soluble tyrosinase mutant. Hence, we demonstrate that EDEM3 provides a unique ERAD timing to misfolded glycoproteins, not only by its mannose trimming activity, but also by the positive and negative feedback modulated by the protease-associated and intrinsically disordered domain, respectively. Full article

(This article belongs to the Special Issue Physio-Pathological Role of ERAD and Its Pharmacological Modulation)

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