STAM and Hrs Down-Regulate Ciliary TRP Receptors

Abstract

Cilia are endowed with membrane receptors, channels, and signaling components whose localization and function must be tightly controlled. In primary cilia of mammalian kidney epithelia and sensory cilia of Caenorhabditis elegans neurons, polycystin-1 (PC1) and transient receptor polycystin-2 channel (TRPP2 or PC2), function together as a mechanosensory receptor-channel complex. Despite the importance of the polycystins in sensory transduction, the mechanisms that regulate polycystin activity and localization, or ciliary membrane receptors in general, remain poorly understood. We demonstrate that signal transduction adaptor molecule STAM-1A interacts with C. elegans LOV-1 (PC1), and that STAM functions with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) on early endosomes to direct the LOV-1-PKD-2 complex for lysosomal degradation. In a stam-1 mutant, both LOV-1 and PKD-2 improperly accumulate at the ciliary base. Conversely, overexpression of STAM or Hrs promotes the removal of PKD-2 from cilia, culminating in sensory behavioral defects. These data reveal that the STAM-Hrs complex, which down-regulates ligand-activated growth factor receptors from the cell surface of yeast and mammalian cells, also regulates the localization and signaling of a ciliary PC1 receptor-TRPP2 complex. INTRODUCTIONCilia are specialized organelles that function in motility (motile or nodal cilia) or sensation (sensory or primary cilia). Several human genetic diseases are linked to defects in cilia formation or function Badano et al., 2006). Ciliary assembly via intraflagellar transport (IFT) and sensory transduction capabilities are evolutionarily conserved . These sensory devices, recently referred to as "antennae" or "nanomachines," transduce a plethora of sensory stimuli and must be fine-tuned both temporally and spatially to execute their cellular functions (Marshall and Nonaka, 2006;Scholey and Anderson, 2006;Singla and Reiter, 2006). Significant advances have been made in understanding cilia biogenesis and the genetic basis of human ciliary disease. In contrast, little is known regarding how cilia perceive, integrate, and transduce multiple extracellular stimuli into precise developmental and physiological responses.Sensory cilia are best known for their roles in photoreception and olfaction, which require G protein-coupled receptors (GPCRs) on the ciliary membrane (Buck and Axel, 1991;Marszalek et al., 2000). Cilia also act in mechanosensory and osmotic capacities and require ciliary localization of transient receptor potential (TRP) ion channels (Tobin et al., 2002;Kim et al., 2003;Nauli et al., 2003). Recently, vertebrate cilia have been shown to mediate not only environmental inputs, but also the Hedgehog (Hh) developmental cue that triggers translocation of the Smoothened (Smo) GPCR into the cilium (May et al., 2005;Huangfu and Anderson, 2006). Vertebrate cilia also express the somatostatin receptor sst3, serotonin 5-HT 6 receptor, platelet-derived growth factor receptor ␣ (PDGFR ␣) and epidermal growth fa...

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

“…Tubby proteins may also regulate endocytosis of signaling proteins (Mukhopadhyay et al 2005(Mukhopadhyay et al , 2007aChen et al 2012). We and others previously showed that defects in endocytosis result in ciliary protein localization defects as well as characteristic ciliary morphological defects (Hu et al 2007;Kaplan et al 2012). Although phenotypes in tub-1 mutants are not identical to those in endocytic mutants, we cannot exclude the possibility that the GPCR mislocalization phenotypes in tub-1 mutants arise from defects in endocytosis.…”

Transmembrane protein OSTA-1 shapes sensory cilia morphology via regulation of intracellular membrane trafficking in C. elegans

“…A number of proteins involved in the exocytic delivery of cilia membrane and protein components have been described, including the BBSome complex and the Rab8 small GTPase (Deretic et al, 1995;Jin et al, 2010;Moritz et al, 2001;Nachury et al, 2007). Although the BBSome has been implicated in ciliary protein removal (Lechtreck et al, 2009), we and others have shown that active clathrin-mediated endocytosis also plays an important role in the retrieval of ciliary membrane and maintenance of cilia morphology (Hu et al, 2007;Kaplan et al, 2012). Thus, ciliary structural and functional homeostasis is likely to be maintained in part via a balance between exocytosis and endocytosis, suggesting that the precise regulation of these pathways is crucial for ciliary morphogenesis.…”

TRPV4-mediated channelopathies

“…[74][75][76][77] Based on the structural information available and existing sequence homology among other TRPs, especially with TRPV members and the manner by which the surface expression of TRP channels are regulated, it can be speculated that proteins like Signal Transducing Adaptor Molecule (STAM), Hrs (which downregulate TRPP2 in C. elegans) and Recombinase Gene Activator (RGA, which regulates cell surface expression of TRPV2) may also be involved in the surface expression of TRPV4. [78][79][80] However, further detailed studies are needed to confirm if these proteins really interact and are involved in the surface expression of TRPV4.…”