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Keratin 8 is a scaffolding and regulatory protein of ERAD complexes

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Abstract

Early recognition and enhanced degradation of misfolded proteins by the endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) cause defective protein secretion and membrane targeting, as exemplified for Z-alpha-1-antitrypsin (Z-A1AT), responsible for alpha-1-antitrypsin deficiency (A1ATD) and F508del-CFTR (cystic fibrosis transmembrane conductance regulator) responsible for cystic fibrosis (CF). Prompted by our previous observation that decreasing Keratin 8 (K8) expression increased trafficking of F508del-CFTR to the plasma membrane, we investigated whether K8 impacts trafficking of soluble misfolded Z-A1AT protein. The subsequent goal of this study was to elucidate the mechanism underlying the K8-dependent regulation of protein trafficking, focusing on the ERAD pathway. The results show that diminishing K8 concentration in HeLa cells enhances secretion of both Z-A1AT and wild-type (WT) A1AT with a 13-fold and fourfold increase, respectively. K8 down-regulation triggers ER failure and cellular apoptosis when ER stress is jointly elicited by conditional expression of the µs heavy chains, as previously shown for Hrd1 knock-out. Simultaneous K8 silencing and Hrd1 knock-out did not show any synergistic effect, consistent with K8 acting in the Hrd1-governed ERAD step. Fractionation and co-immunoprecipitation experiments reveal that K8 is recruited to ERAD complexes containing Derlin2, Sel1 and Hrd1 proteins upon expression of Z/WT-A1AT and F508del-CFTR. Treatment of the cells with c407, a small molecule inhibiting K8 interaction, decreases K8 and Derlin2 recruitment to high-order ERAD complexes. This was associated with increased Z-A1AT secretion in both HeLa and Z-homozygous A1ATD patients’ respiratory cells. Overall, we provide evidence that K8 acts as an ERAD modulator. It may play a scaffolding protein role for early-stage ERAD complexes, regulating Hrd1-governed retrotranslocation initiation/ubiquitination processes. Targeting K8-containing ERAD complexes is an attractive strategy for the pharmacotherapy of A1ATD.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Dr. Eric Chevet for A1AT/Z-A1AT plasmids, Annemarie van Schadewijk for help in culturing the HBE cells, and Anush Bakhunts for µs expressing HeLa cells. We thank Dr Grazyna Faure, Dr. Stefano Fumagali and Dr Olivier Namy for helpful discussions and advices. We thank Muriel Girard, Dominique Debray, Francois Vermeulen, Linda Boulanger and Marianne Schulte for providing the A1AT/Z-A1AT primary cells and Prof. Hideki Nishitoh for HEK Derlin1/2 KO cells. We thank Dr Chiara Guerrera and Dr Joanna Lipecka from Proteomic SFR Necker core facility for protein identifications. We are very grateful to Isabelle Hatin for technical assistance, and the cell imaging platform for assistance with microscopy experiments. The authors are very grateful to Mucoviscidose ABCF2 for support.

Funding

This work was supported by Agence Nationale de la Recherche (ANR-13-BSV1-0019–01, and ANR-18-CE14-0004) and Chancellerie des universites de Paris (legs Poix, 15LEG005_9UMS1151).

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  1. Benoit Chevalier, Aiswarya Premchandar, Alexandre Hinzpeter, Isabelle Sermet-Gaudelus have equally participated.

Authors and Affiliations

  1. Inserm, U1151, CNRS UMR 8253, Université de Paris, 160 rue de Vaugirard, 75015, Paris, France

    Iwona Maria Pranke, Benoit Chevalier, Nesrine Baatallah, Kamil F. Tomaszewski, Sara Bitam, Danielle Tondelier, Anita Golec, Alexandre Hinzpeter, Isabelle Sermet-Gaudelus & Aleksander Edelman

  2. Cystic Fibrosis Center, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France

    Isabelle Sermet-Gaudelus

  3. Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02106, Warsaw, Poland

    Aiswarya Premchandar & Michal Dadlez

  4. Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

    Jan Stolk & Pieter S. Hiemstra

  5. Department of Physiology, McGill University, Montréal, QC, Canada

    Gergely L. Lukacs

  6. Department of Biochemistry, McGill University, Montréal, QC, Canada

    Gergely L. Lukacs

  7. UCL Respiratory and the Institute of Structural and Molecular Biology, University College London, London, WC1E 6JF, UK

    David A. Lomas & James A. Irving

  8. Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France

    Agnes Delaunay-Moisan

  9. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy

    Eelco van Anken

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  1. Iwona Maria Pranke
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Contributions

IMP participated in the experimental strategy preparation, conceived the protocols, performed experiments, analyzed and interpreted results and wrote the manuscript; BC performed biochemistry experiments; AP performed mass spectrometry experiments and analysis; NB and KFT performed some biochemistry experiments; SB established the shRNAK8 cell line; DT performed cell biology experiments; AG participated in primary cell culture and biochemistry experiments; JS provided the A1AT/Z-A1AT primary cells; GLL participated in the experimental strategy preparation; PSH, MD and DAL participated in the writing of the manuscript; JAI participated in preparing the experimental strategy and edited the manuscript; AD-M participated in designing the experimental strategy and editing of the manuscript; EA participated in preparing the experimental strategy; AH performed cell biology experiments and wrote the manuscript; IS-G participated in preparing the experimental strategy and writing of the manuscript; AE conceived of and coordinated the project and wrote the manuscript. All authors reviewed the manuscript and approved its submission.

Corresponding authors

Correspondence to Iwona Maria Pranke or Aleksander Edelman.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Ile-de-France 2 (CPP IDF2: 2010–05-03–3). Written informed consent was obtained from all individual participants included in the study or parents of children under 16.

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This data has been published on a pre-print server bioRXiv ('https://www.biorxiv.org/content/10.1101/2022.02.01.478623v1').

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Pranke, I.M., Chevalier, B., Premchandar, A. et al. Keratin 8 is a scaffolding and regulatory protein of ERAD complexes. Cell. Mol. Life Sci. 79, 503 (2022). https://doi.org/10.1007/s00018-022-04528-3

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