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The Rilp-like proteins Rilpl1 and Rilpl2 regulate ciliary membrane content.

ABSTRACT: The primary cilium is a microtubule-based structure found in most cell types in mammals. Disruption of cilium function causes a diverse set of human diseases collectively known as ciliopathies. We report that Rab effector-related proteins Rab-interacting lysosomal protein-like 1 (Rilpl1) and Rilpl2 regulate protein localization in the primary cilium. Rilpl2 was initially identified as up-regulated in ciliating mouse tracheal epithelial cells. Rilpl1 and Rilpl2 both localize to the primary cilium and centrosome, Rilpl1 specifically to the distal end of the mother centriole. Live-cell microscopy reveals that Rilpl2 primary cilium localization is dynamic and that it is associated with tubulovesicular structures at the base of the cilium. Depletion of Rilpl1 and Rilpl2 results in accumulation of signaling proteins in the ciliary membrane and prevents proper epithelial cell organization in three-dimensional culture. These data suggest that Rilp-like proteins function in regulation of ciliary membrane protein concentration by promoting protein removal from the primary cilium.

SUBMITTER: Schaub JR

PROVIDER: S-EPMC3571868 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The Rilp-like proteins Rilpl1 and Rilpl2 regulate ciliary membrane content.

Schaub Johanna R JR Stearns Tim T

Molecular biology of the cell 20121221 4

The primary cilium is a microtubule-based structure found in most cell types in mammals. Disruption of cilium function causes a diverse set of human diseases collectively known as ciliopathies. We report that Rab effector-related proteins Rab-interacting lysosomal protein-like 1 (Rilpl1) and Rilpl2 regulate protein localization in the primary cilium. Rilpl2 was initially identified as up-regulated in ciliating mouse tracheal epithelial cells. Rilpl1 and Rilpl2 both localize to the primary cilium ...[more]

PMID: 23264467

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Project description:Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health and disease are maintained by a complex ensemble of intracellular targeting, scaffolding, recycling, and degradation pathways. Surprisingly, despite decades of research linking dysfunction in membrane protein trafficking with human cardiovascular disease, essentially nothing is known regarding the molecular identity or function of these intracellular targeting pathways in excitable cardiomyocytes.We sought to discover novel pathways for membrane protein targeting in primary cardiomyocytes.We report the initial characterization of a large family of membrane trafficking proteins in human heart. We used a tissue-wide screen for novel ankyrin-associated trafficking proteins and identified 4 members of a unique Eps15 homology (EH) domain-containing protein family (EHD1, EHD2, EHD3, EHD4) that serve critical roles in endosome-based membrane protein targeting in other cell types. We show that EHD1-4 directly associate with ankyrin, provide the first information on the expression and localization of these molecules in primary cardiomyocytes, and demonstrate that EHD1-4 are coexpressed with ankyrin-B in the myocyte perinuclear region. Notably, the expression of multiple EHD proteins is increased in animal models lacking ankyrin-B, and EHD3-deficient cardiomyocytes display aberrant ankyrin-B localization and selective loss of Na/Ca exchanger expression and function. Finally, we report significant modulation of EHD expression following myocardial infarction, suggesting that these proteins may play a key role in regulating membrane excitability in normal and diseased heart.Our findings identify and characterize a new class of cardiac trafficking proteins, define the first group of proteins associated with the ankyrin-based targeting network, and identify potential new targets to modulate membrane excitability in disease. Notably, these data provide the first link between EHD proteins and a human disease model.

Dataset Information

The Rilp-like proteins Rilpl1 and Rilpl2 regulate ciliary membrane content.

Publications

The Rilp-like proteins Rilpl1 and Rilpl2 regulate ciliary membrane content.

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