RT Journal Article
SR Electronic
T1 Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.09.459609
DO 10.1101/2021.09.09.459609
A1 Céline Revenu
A1 Marianna Parlato
A1 Marion Rosello
A1 Karine Duroure
A1 Rémi Duclaux-Loras
A1 Ophélie Nicolle
A1 Marie-Thérèse Prospéri
A1 Julie Stoufflet
A1 Juliette Vougny
A1 Corinne Lebreton
A1 Priscilla Lépine
A1 Grégoire Michaux
A1 Nadine Cerf-Benssusan
A1 Evelyne Coudrier
A1 Filippo Del Bene
YR 2021
UL http://biorxiv.org/content/early/2021/09/10/2021.09.09.459609.abstract
AB 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 StatementThe authors have declared no competing interest.