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Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis

View ORCID ProfileCéline Revenu, Marianna Parlato, View ORCID ProfileMarion Rosello, Karine Duroure, Rémi Duclaux-Loras, Ophélie Nicolle, Marie-Thérèse Prospéri, Julie Stoufflet, Juliette Vougny, Corinne Lebreton, Priscilla Lépine, Grégoire Michaux, Nadine Cerf-Benssusan, View ORCID ProfileEvelyne Coudrier, View ORCID ProfileFilippo Del Bene
doi: https://doi.org/10.1101/2021.09.09.459609
Céline Revenu
1Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75248 Paris Cedex 05, France
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Marianna Parlato
2INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, 75015 Paris, France
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Marion Rosello
1Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75248 Paris Cedex 05, France
3Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France
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Karine Duroure
1Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75248 Paris Cedex 05, France
3Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France
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Rémi Duclaux-Loras
2INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, 75015 Paris, France
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Ophélie Nicolle
5CNRS, UMR6290, Institut de Génétique et Développement de Rennes, F-35043 15 Rennes, France
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Marie-Thérèse Prospéri
4Institut Curie, PSL Research University, CNRS UMR144, 75248 Paris Cedex 05, France
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Julie Stoufflet
1Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75248 Paris Cedex 05, France
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Juliette Vougny
1Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75248 Paris Cedex 05, France
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Corinne Lebreton
2INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, 75015 Paris, France
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Priscilla Lépine
4Institut Curie, PSL Research University, CNRS UMR144, 75248 Paris Cedex 05, France
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Grégoire Michaux
5CNRS, UMR6290, Institut de Génétique et Développement de Rennes, F-35043 15 Rennes, France
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Nadine Cerf-Benssusan
2INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, 75015 Paris, France
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Evelyne Coudrier
4Institut Curie, PSL Research University, CNRS UMR144, 75248 Paris Cedex 05, France
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Filippo Del Bene
1Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75248 Paris Cedex 05, France
3Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France
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  • For correspondence: filippo.del-bene@inserm.fr
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Abstract

Vesicle trafficking and the establishment of apico-basal polarity are essential processes in epithelium morphogenesis. Myosin-1b, an actin-motor able to bind membranes, regulates membrane shaping and vesicle trafficking. Here, we investigate Myosin-1b function in gut morphogenesis and congenital disorders using cell line and zebrafish larvae as well as patient biopsies. In a 3D Caco-2 cyst model, lumen formation is impaired in absence of Myosin-1b. In zebrafish, both Morpholino knock-down and genetic mutation of myo1b result in intestinal bulb epithelium folding defects associated with vesicle accumulation, reminiscent of a villous atrophy phenotype. We show that Myosin-1b interacts with the chaperone UNC45A, genetic deletion of which also results in gut folding defects in zebrafish. Loss of function mutations in UNC45A have been reported in complex hereditary syndromes, notably exhibiting intestinal disorders associated with villous atrophy. In UNC45A-depleted cells and in patient biopsies, Myosin-1b protein level is strikingly decreased. The appearance of Myosin-1b aggregates upon proteasome inhibition in cells points at a degradation mechanism of misfolded Myosin-1b in the absence of its chaperone. In conclusion, Myosin-1b plays an unexpected role in the development of the intestinal epithelium folds or villi downstream UNC45A, establishing its role in the gut defects reported in UNC45A patients.

Summary statement Myosin-1b is important for intestinal epithelium folding during zebrafish development and participates in the villous atrophy clinical manifestation downstream UNC45A loss of function.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 10, 2021.
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Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis
Céline Revenu, Marianna Parlato, Marion Rosello, Karine Duroure, Rémi Duclaux-Loras, Ophélie Nicolle, Marie-Thérèse Prospéri, Julie Stoufflet, Juliette Vougny, Corinne Lebreton, Priscilla Lépine, Grégoire Michaux, Nadine Cerf-Benssusan, Evelyne Coudrier, Filippo Del Bene
bioRxiv 2021.09.09.459609; doi: https://doi.org/10.1101/2021.09.09.459609
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Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis
Céline Revenu, Marianna Parlato, Marion Rosello, Karine Duroure, Rémi Duclaux-Loras, Ophélie Nicolle, Marie-Thérèse Prospéri, Julie Stoufflet, Juliette Vougny, Corinne Lebreton, Priscilla Lépine, Grégoire Michaux, Nadine Cerf-Benssusan, Evelyne Coudrier, Filippo Del Bene
bioRxiv 2021.09.09.459609; doi: https://doi.org/10.1101/2021.09.09.459609

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