USP2-45 Is a Circadian Clock Output Effector Regulating Calcium Absorption at the Post-Translational Level.

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Serval ID
serval:BIB_336F0A68F654
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
USP2-45 Is a Circadian Clock Output Effector Regulating Calcium Absorption at the Post-Translational Level.
Journal
Plos One
Author(s)
Pouly D., Chenaux S., Martin V., Babis M., Koch R., Nagoshi E., Katanaev V.L., Gachon F., Staub O.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
11
Number
1
Pages
e0145155
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
The mammalian circadian clock influences most aspects of physiology and behavior through the transcriptional control of a wide variety of genes, mostly in a tissue-specific manner. About 20 clock-controlled genes (CCGs) oscillate in virtually all mammalian tissues and are generally considered as core clock components. One of them is Ubiquitin-Specific Protease 2 (Usp2), whose status remains controversial, as it may be a cogwheel regulating the stability or activity of core cogwheels or an output effector. We report here that Usp2 is a clock output effector related to bodily Ca2+ homeostasis, a feature that is conserved across evolution. Drosophila with a whole-body knockdown of the orthologue of Usp2, CG14619 (dUsp2-kd), predominantly die during pupation but are rescued by dietary Ca2+ supplementation. Usp2-KO mice show hyperabsorption of dietary Ca2+ in small intestine, likely due to strong overexpression of the membrane scaffold protein NHERF4, a regulator of the Ca2+ channel TRPV6 mediating dietary Ca2+ uptake. In this tissue, USP2-45 is found in membrane fractions and negatively regulates NHERF4 protein abundance in a rhythmic manner at the protein level. In clock mutant animals (Cry1/Cry2-dKO), rhythmic USP2-45 expression is lost, as well as the one of NHERF4, confirming the inverse relationship between USP2-45 and NHERF4 protein levels. Finally, USP2-45 interacts in vitro with NHERF4 and endogenous Clathrin Heavy Chain. Taken together these data prompt us to define USP2-45 as the first clock output effector acting at the post-translational level at cell membranes and possibly regulating membrane permeability of Ca2+.
Keywords
Absorption, Physiological, Animals, Calcium/metabolism, Circadian Clocks, Clathrin Heavy Chains/metabolism, Cryptochromes/metabolism, Drosophila melanogaster/metabolism, HEK293 Cells, Homeostasis, Humans, Hypercalciuria/metabolism, Intestinal Mucosa/metabolism, Locomotion, Male, Membranes/metabolism, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Phosphoproteins/metabolism, Protein Binding, Protein Processing, Post-Translational, Sodium-Hydrogen Antiporter/metabolism, Ubiquitin-Specific Proteases/metabolism, Up-Regulation
Pubmed
Web of science
Open Access
Yes
Create date
02/02/2016 18:12
Last modification date
20/08/2019 14:19
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