Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not cleavage at GPS site

Su, Xiaoqiang; Yao, Gang; El-Jouni, Wassim; Luo, Chong; Tabari, Azadeh; Zhou, Jing

doi:10.1242/jcs.160556

Cited by 36 publications

(39 citation statements)

References 69 publications

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“…Through a systematic analysis, we have further identified multiple sequences in the PC1 C tail, including the coiled-coil domain, that are involved in the regulation of PC1 ciliary trafficking. Notably, the first identified CTS for PC1, the VxP motif at the end of PC1 C tail, is completely dispensable for full-length PC1 trafficking, although we found that it is capable of driving CD16.7 to cilia as previously described by Su et al (15). CD16.7 is a well-characterized chimeric protein consisting of the human CD16 extracellular domain and the human CD7 transmembrane domain, and is frequently used for identifying functional motifs, domains, and sequences (19,(30)(31)(32).…”

Section: The 42-residue Fragment In the Pc1 C-terminal Cytoplasmic Tasupporting

confidence: 77%

“…These constructs are referred to as mini-constructs in this study to distinguish them from the full-length PC1 constructs. Unlike full-length PC1, which requires PC2 to reach cilia (14,15), we found that the ciliary trafficking of chimeric PC1 proteins was independent of PC2 (Supplemental Fig. S1).…”

Section: The 42-residue Fragment In the Pc1 C-terminal Cytoplasmic Tamentioning

confidence: 90%

“…CD16.7 is a well-characterized chimeric protein consisting of the human CD16 extracellular domain and the human CD7 transmembrane domain, and is frequently used for identifying functional motifs, domains, and sequences (19,(30)(31)(32). Because the coiled-coil domain cannot target chimeric protein to cilia, we hypothesized that the full-length PC1 and chimeric protein might traffic to cilia via different mechanisms (15). Based on this hypothesis, we next examined whether PC2 regulates chimeric protein trafficking by expressing these chimeric constructs in both WT and PC2-KO cells and costaining the chimeric protein with a cilium marker.…”

Section: The 42-residue Fragment In the Pc1 C-terminal Cytoplasmic Tamentioning

confidence: 99%

“…It has been shown that PC1 colocalizes with polycystin-2 (PC2; encoded by PKD2) on the primary cilium where it functions as an atypical GPCR and mediates mechanosensation (9)(10)(11). Recent studies have implied that impaired ciliary trafficking of polycystins contributes to the pathogenesis of ADPKD (12)(13)(14)(15). However, the mechanisms by which PC1 is targeted to cilia remain poorly understood.…”

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confidence: 99%

“…Previous studies have reported that the PC1 CTT contains the VxP motif that targets rhodopsin to cilia (18), and this VxP motif also targets a small fragment of PC1 to cilia in an ADP ribosylation factor 4 (Arf4)-dependent manner (19). However, this VxP motif is not required for full-length PC1 targeting to cilia (15).…”

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confidence: 99%

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Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking

Luo

et al. 2019

FASEB j.

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder causing renal failure. Mutations of polycystic kidney disease 1 (PKD1) account for most ADPKD cases. Defective ciliary localization of polycystin‐1 (PC1), a large integral membrane protein encoded by PKD1, underlies the pathogenesis of a subgroup of patients with ADPKD. However, the mechanisms by which PC1 and other ciliary proteins traffic to the primary cilium remain poorly understood. A ciliary targeting sequence (CTS) that resides in ciliary receptors is considered to function in the process. It has been reported that the VxP motif in the intracellular C‐terminal tail of PC1 functions as a CTS in an ADP ribosylation factor 4 (Arf4)/ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1)–dependent manner. However, other recent studies have revealed that this motif is dispensable for PC1 trafficking to cilia. In this study, we identified a novel CTS consisting of 8 residues (RHKVRFEG) in the PC1 C tail. We found that this motif is sufficient to bind protein phosphatase 1 (PP1)α, a ubiquitously expressed phosphatase in the phosphoprotein phosphatase (PPP) family. Mutations in this CTS motif disrupt binding with PP1α and impair ciliary localization of PC1. Additionally, short hairpin RNA–mediated knockdown of PP1α results in reduced ciliary localization of PC1 and elongated cilia, suggesting a role for PP1α in the regulation of ciliary structure and function.—Luo, C., Wu, M., Su, X., Yu, F., Brautigan, D. L., Chen, J., Zhou, J. Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking. FASEB J. 33, 9945–9958 (2019). http://www.fasebj.org

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Section: The 42-residue Fragment In the Pc1 C-terminal Cytoplasmic Tasupporting

confidence: 77%

Section: The 42-residue Fragment In the Pc1 C-terminal Cytoplasmic Tamentioning

confidence: 90%

Section: The 42-residue Fragment In the Pc1 C-terminal Cytoplasmic Tamentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking

Luo

et al. 2019

FASEB j.

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BMP4 regulates asymmetric Pkd2 distribution in mouse nodal immotile cilia and ciliary mechanosensing required for left–right determination

Katoh,

Lange,

Nakajima

et al. 2024

Developmental Dynamics

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BackgroundMouse nodal immotile cilia mechanically sense the bending direction for left–right (L–R) determination and activate the left‐side‐specific signaling cascade, leading to increased Nodal activity. Asymmetric distribution of Pkd2, a crucial channel for L–R determination, on immotile cilia has been reported recently. However, the causal relationship between the asymmetric Pkd2 distribution and direction‐dependent flow sensing is not well understood. Furthermore, the underlying molecular mechanism directing this asymmetric Pkd2 distribution remains unclear.ResultsThe effects of several recombinant proteins and inhibitors on the Pkd2 distribution were analyzed using super‐resolution microscopy. Notably, bone morphogenetic protein 4 (BMP4) affected the Pkd2 distribution. Additionally, three‐dimensional manipulation of nodal immotile cilia using optical tweezers revealed that excess BMP4 caused defects in the mechanosensing ability of the cilia.ConclusionsExperimental data together with model calculations suggest that BMP4 regulates the asymmetric distribution of Pkd2 in nodal immotile cilia, thereby affecting the ability of these cilia to sense the bending direction for L–R determination. This study, for the first time, provides insight into the relationship between the asymmetric protein distribution in cilia and their function.

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Primary Cilia in Cystic Kidney Disease

Avasthi

Maser

Tran

2017

Results and Problems in Cell Differentiation

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Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.

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Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not cleavage at GPS site

Cited by 36 publications

References 69 publications

Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking

Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin‐1 and regulates polycystin‐1 trafficking

BMP4 regulates asymmetric Pkd2 distribution in mouse nodal immotile cilia and ciliary mechanosensing required for left–right determination

Primary Cilia in Cystic Kidney Disease

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