UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking
Rémi Duclaux-Loras
(1, 2)
,
Corinne Lebreton
(1)
,
Jérémy Berthelet
(3)
,
Fabienne Charbit-Henrion
(1, 2)
,
Ophélie Nicolle
(4)
,
Celine Revenu de Courtils
(5, 6)
,
Stephanie Waich
(7)
,
Taras Valovka
(7)
,
Anis Khiat
(1)
,
Marion Rabant
(2)
,
Caroline Racine
(8, 9)
,
Ida Chiara Guerrera
(10)
,
Julia Baptista
(11, 12)
,
Maxime M Mahe
(13)
,
M Hess
(7)
,
Beatrice Durel
(10)
,
Nathalie Lefort
(1)
,
Céline Banal
(1)
,
Mélanie Parisot
(10, 1)
,
Cecile Talbotec
(2)
,
Florence Lacaille
(2)
,
Emmanuelle Ecochard-Dugelay
(14)
,
Arzu Meltem Demir
(15)
,
Georg F. Vogel
(7)
,
Laurence Faivre
(2)
,
Astor Rodrigues
(16)
,
D Fowler
(16)
,
Andreas R Janecke
(7)
,
Thomas Mueller
(7)
,
Lukas A Huber
(7)
,
Fernando Rodrigues Lima
(17)
,
Frank M. Ruemmele
(2)
,
Holm H. Uhlig
(16)
,
Filippo Del Bene
(6, 5)
,
Grégoire Michaux
(4, 18, 19)
,
Nadine Cerf-Bensussan
(1)
,
Marianna Parlato
(1)
1
Imagine - U1163 -
Imagine - Institut des maladies génétiques (IHU)
2 Hôpital Necker - Enfants Malades [AP-HP]
3 EDC - Centre épigénétique et destin cellulaire
4 IGDR - Institut de Génétique et Développement de Rennes
5 Génétique et Biologie du Développement
6 Institut de la Vision
7 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
8 Equipe GAD (LNC - U1231)
9 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
10 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
11 Plymouth University
12 Royal Devon and Exeter NHS Foundation Trust [UK]
13 TENS - The Enteric Nervous System in gut and brain disorders [U1235]
14 Hôpital Robert Debré
15 Ankara Training and Research Hospital
16 John Radcliffe Hospital [Oxford University Hospital]
17 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
18 UR - Université de Rennes
19 CNRS - Centre National de la Recherche Scientifique
2 Hôpital Necker - Enfants Malades [AP-HP]
3 EDC - Centre épigénétique et destin cellulaire
4 IGDR - Institut de Génétique et Développement de Rennes
5 Génétique et Biologie du Développement
6 Institut de la Vision
7 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
8 Equipe GAD (LNC - U1231)
9 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
10 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
11 Plymouth University
12 Royal Devon and Exeter NHS Foundation Trust [UK]
13 TENS - The Enteric Nervous System in gut and brain disorders [U1235]
14 Hôpital Robert Debré
15 Ankara Training and Research Hospital
16 John Radcliffe Hospital [Oxford University Hospital]
17 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
18 UR - Université de Rennes
19 CNRS - Centre National de la Recherche Scientifique
Taras Valovka
- Fonction : Auteur
- PersonId : 892100
Ida Chiara Guerrera
- Fonction : Auteur
- PersonId : 792780
- ORCID : 0000-0002-4832-6793
- IdRef : 200820249
Julia Baptista
- Fonction : Auteur
- PersonId : 1156051
- ORCID : 0000-0003-0915-5028
Maxime M Mahe
- Fonction : Auteur
- PersonId : 1137577
Nathalie Lefort
- Fonction : Auteur
- PersonId : 793613
- ORCID : 0000-0002-2484-6057
Mélanie Parisot
- Fonction : Auteur
- PersonId : 778147
- ORCID : 0000-0003-4312-2035
Thomas Mueller
- Fonction : Auteur
- PersonId : 756111
- ORCID : 0000-0003-1862-7357
Fernando Rodrigues Lima
- Fonction : Auteur
- PersonId : 1140380
Grégoire Michaux
- Fonction : Auteur
- PersonId : 738864
- IdHAL : gregoire-michaux
- ORCID : 0000-0003-1222-5461
- IdRef : 060892854
Nadine Cerf-Bensussan
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 9864
- IdHAL : nadinecerf-bensussan
- ORCID : 0000-0003-0665-1245
- IdRef : 032175221
Connectez-vous pour contacter l'auteur
Marianna Parlato
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 934325
Connectez-vous pour contacter l'auteur
Résumé
Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.
Domaines
Sciences du Vivant [q-bio]Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking
|
Résumé |
en
Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45A(KO) Caco-2 cells. In keeping with impaired myosin VB function, UNC45A(KO) Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45A(KO) 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.
|
Auteur(s) |
Rémi Duclaux-Loras
1, 2
, Corinne Lebreton
1
, Jérémy Berthelet
3
, Fabienne Charbit-Henrion
1, 2
, Ophélie Nicolle
4
, Celine Revenu de Courtils
5, 6
, Stephanie Waich
7
, Taras Valovka
7
, Anis Khiat
1
, Marion Rabant
2
, Caroline Racine
8, 9
, Ida Chiara Guerrera
10
, Julia Baptista
11, 12
, Maxime M Mahe
13
, M Hess
7
, Beatrice Durel
10
, Nathalie Lefort
1
, Céline Banal
1
, Mélanie Parisot
10, 1
, Cecile Talbotec
2
, Florence Lacaille
2
, Emmanuelle Ecochard-Dugelay
14
, Arzu Meltem Demir
15
, Georg F. Vogel
7
, Laurence Faivre
2
, Astor Rodrigues
16
, D Fowler
16
, Andreas R Janecke
7
, Thomas Mueller
7
, Lukas A Huber
7
, Fernando Rodrigues Lima
17
, Frank M. Ruemmele
2
, Holm H. Uhlig
16
, Filippo Del Bene
6, 5
, Grégoire Michaux
4, 18, 19
, Nadine Cerf-Bensussan
1
, Marianna Parlato
1
1
Imagine - U1163 -
Imagine - Institut des maladies génétiques (IHU)
( 1004662 )
- IHU Imagine,
156 rue de Vaugirard, 75015 PARIS
et
24 Boulevard du Montparnasse, 75015 Paris
- France
2
Hôpital Necker - Enfants Malades [AP-HP]
( 414766 )
- 149 Rue de Sèvres 75015 Paris
- France
3
EDC -
Centre épigénétique et destin cellulaire
( 1004995 )
- Université Paris Diderot Bât. Lamarck case postale 7042 75205 Paris CEDEX 13
- France
4
IGDR -
Institut de Génétique et Développement de Rennes
( 187162 )
- Faculté de Médecine - CS 34317 2 Av du Professeur Léon Bernard 35043 Rennes Cedex
- France
5
Génétique et Biologie du Développement
( 541962 )
- Institut Curie - Section Recherche Pole de Biologie du Développement et Cancer 26, rue d'Ulm 75248 PARIS Cedex 05
- France
6
Institut de la Vision
( 541916 )
- 17 Rue Moreau, 75012 Paris
- France
7
IMU -
Innsbruck Medical University = Medizinische Universität Innsbruck
( 465250 )
- Innrain 52, Christoph-Probst-Platz, 6020 Innsbruck
- Autriche
8
Equipe GAD (LNC - U1231)
( 1096461 )
- Université de Bourgogne - Faculté de médecine - 7, Bld Jeanne d'Arc - BP 87900 - 21079 DIJON CEDEX
- France
9
CHU Dijon -
Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
( 300924 )
- CHU Dijon - 14 rue Paul Gaffarel - 21079 Dijon
- France
10
UAR 3633 / US24 -
Structure Fédérative de Recherche Necker
( 1004800 )
- 14 rue Maria Da Silva CS61431 75014 Paris
- France
11
Plymouth University
( 469055 )
- Drake Circus Plymouth Devon PL4 8AA United Kingdom
- Royaume-Uni
12
Royal Devon and Exeter NHS Foundation Trust [UK]
( 533970 )
- Barrack Road, Exeter, EX2 5DW.
- Royaume-Uni
13
TENS -
The Enteric Nervous System in gut and brain disorders [U1235]
( 1088539 )
- Faculté de Médecine,
1 rue Gaston Veil,
44035 Nantes
- France
14
Hôpital Robert Debré
( 300089 )
-
- France
15
Ankara Training and Research Hospital
( 333418 )
-
- France
16
John Radcliffe Hospital [Oxford University Hospital]
( 331576 )
- Headley Way, Headington,
Oxford OX3 9DU
- Royaume-Uni
17
BFA (UMR_8251 / U1133) -
Unité de Biologie Fonctionnelle et Adaptative
( 1005042 )
- Université Paris Diderot, Bât. Buffon, 4 rue Marie-Andrée Lagroua Weill-Hallé, case postale 7081 , 75205 Paris cedex 13
- France
18
UR -
Université de Rennes
( 105160 )
- Campus de Beaulieu, 263 avenue Général Leclerc, CS 74205, 35042 RENNES CEDEX
- France
19
CNRS -
Centre National de la Recherche Scientifique
( 441569 )
- France
|
Licence |
Paternité
|
Langue du document |
Anglais
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Volume |
132
|
Numéro |
10
|
Page/Identifiant |
-
|
Nom de la revue |
|
Date de publication |
2022-05-16
|
Domaine(s) |
|
Financement |
|
Projet(s) ANR |
|
Mots-clés |
en
Epithelial transport of ions and water, Gastroenterology
|
DOI | 10.1172/JCI154997 |
Pubmed Id | 35575086 |
PubMed Central | PMC9106349 |
Origine :
Fichiers éditeurs autorisés sur une archive ouverte
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