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

Luo, Chong; Su, Xiaoqiang; Yu, Fangyan; Brautigan, David L.; Chen, Jianghua; Zhou, Jing

doi:10.1096/fj.201900338r

Cited by 13 publications

(13 citation statements)

References 65 publications

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“… 48 , 49 During the transport of glucose into cells, glycogen synthesis, oxidative decomposition and other metabolic processes, protein phosphatase 1 (PP1) pathway is the most important metabolic process for synthesizing glucose into glycogen, accounting for about 60 ~ 70%. 50 In the state of insulin resistance, the activation effect of insulin on PPP1CC is weakened, thus reducing the activity of GYS1, resulting in decreased glycogen synthesis and increased blood glucose in T2D patients. 51 Our investigation further corroborated that GYS1 and PPP1CC were target genes of miR-140-5p and had effects on the glycose consumption and glycose uptake, which provided a novel mechanism through which miR-140-5p could regulate the insulin resistance in diabetes mellitus.…”

Section: Discussionmentioning

confidence: 99%

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

Yan

Wang

et al. 2021

DMSO

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Background Much attention has been paid to the regulatory role of microRNA (miRNA) in insulin resistance. Nevertheless, how miR-140-5p regulates insulin resistance remains unclear. In this research, we aim to investigate the roles of miR-140-5p in insulin resistance. Methods qRT-PCR is used to analyze the expression level of miR-140-5p in insulin-resistant HepG2 cells. Glucose consumption and glucose uptake are detected to study the effect of miR-140-5p knockdown in insulin-resistant HepG2 cells and miR-140-5p overexpression in HepG2 cells. Bioinformatic analysis, luciferase reporter assay and confirmatory experiments are applied to identify the target gene bound with miR-140-5p and study the effect of miR-140-5p on the downstream substrates of target genes. Rescue experiments have verified the roles of miR-140-5p and target gene in glucose metabolism. Results The expression level of miR-140-5p was upregulated in insulin-resistant HepG2 cells and was significantly correlated with cellular glucose metabolism. Functionally, miR-140-5p overexpression induced impairment of glucose consumption and glucose uptake. Besides, bioinformatics analysis indicated that glycogen synthetase (GYS1) and protein phosphatase 1 catalytic subunit gamma (PPP1CC) were the target genes of miR-140-5p. Western blotting and qRT-PCR results revealed a negative correlation between GYS1, PPP1CC and miR-140-5p. The glycogen detection results showed that miR140-5p inhibited the production of the downstream substrates of the target gene. Rescue experiments showed that inhibition of GYS1 or PPP1CC partially enhanced the insulin-resistant effects of miR-140-5p knockdown in insulin-resistant HepG2 cells. Conclusion miR-140-5p overexpression augments the development of insulin resistance and miR-140-5p may be served as a therapeutic target of metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

Yan

Wang

et al. 2021

DMSO

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“…Subsequent studies that examined the traffic of full-length PC1 showed that the VxP motif is dispensable for ciliary delivery, that full-length PC1 targeting to cilia is not perturbed by ARF4 depletion, and that endogenous PC1 does not bind ARF4 in collecting duct cells (88,89,149,165). Such differences might be due to the requirement for PC2 in traffic of full-length PC1 but not the chimeric PC1 protein (109,149).…”

Section: Arf4mentioning

confidence: 99%

ARF family GTPases with links to cilia

Fisher

Kuna

Caspary

et al. 2020

American Journal of Physiology-Cell Physiology

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The ARF superfamily of regulatory GTPases, including both the ARF and ARL proteins, control a multitude of cellular functions including aspects of vesicular traffic, lipid metabolism, mitochondrial architecture, the assembly and dynamics of the microtubule and actin cytoskeletons, and other pathways in cell biology. Considering their general utility, it is perhaps not surprising that increasingly ARF/ARLs have been found in connection to primary cilia. Here, we critically evaluate the current knowledge of the role four ARF/ARLs (ARF4, ARL3, ARL13B and ARL6) play in cilia and highlight key missing information that would help move our understanding forward. Importantly, these GTPases are themselves regulated by guanine nucleotide exchange factors (GEFs) that activate them and by GTPase activating proteins (GAPs) that act as both effectors and terminators of signaling. We believe that the identification of the GEFs and GAPs and better models of the actions of these GTPases and their regulators will provide a much deeper understanding and appreciation of the mechanisms that underly ciliary functions and the causes of a number of human ciliopathies.

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“…Protein phosphatase one interacts with AKAP220 primarily through its KVQF motif ( Schillace and Scott, 1999 ) and has recently been implicated in trafficking of polycystin-1 to cilia ( Luo et al, 2019 ). We used CRISPR-Cas9 gene editing to generate a knock-in cell line where the phosphatase-targeting motif was replaced by a TATA sequence ( Figure 3A & B ; Figure 3—figure supplement 1A & B ).…”

Section: Resultsmentioning

confidence: 99%

Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

Gopalan

Omar

Roy

et al. 2021

eLife

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Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

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

Cited by 13 publications

References 65 publications

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

ARF family GTPases with links to cilia

Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

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