Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner

Wang, Wei; Silva, Luciane M.; Wang, Henry H.; Kavanaugh, Matthew A.; Pottorf, Tana S.; Allard, Bailey A.; Jacobs, Damon T.; Dong, Rouchen; Cornelius, Joseph T.; Chaturvedi, Aakriti; Pritchard, Michele T.; Sharma, Madhulika; Slawson, Chad; Wallace, Darren P.; Calvet, James P.; Tran, Pamela V.

doi:10.1101/2020.04.26.061796

Cited by 2 publications

(2 citation statements)

References 82 publications

(137 reference statements)

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“…In line with a role of TULP3 in trafficking multiple cargoes, TULP3 and IFT-A have been implicated in neural tube patterning (Legue and Liem, 2020;Liem et al, 2012;Mukhopadhyay et al, 2013;Norman et al, 2009;Qin et al, 2011), renal cystogenesis (Hwang et al, 2019;Legue and Liem, 2019;Wang et al, 2020) and adipogenesis (Hilgendorf et al, 2019;Wu et al, 2020).…”

Section: Introductionmentioning

confidence: 79%

Interactions between TULP3 tubby domain cargo site and ARL13B amphipathic helix promote lipidated protein transport to cilia

Palicharla

Hwang

Somatilaka

et al. 2021

Preprint

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The tubby family protein-TULP3 coordinates with the intraflagellar transport complex-A (IFT-A) in trafficking certain transmembrane proteins to cilia. These transmembrane cargoes have short motifs that are necessary and sufficient for TULP3-mediated trafficking. However, whether TULP3 regulates trafficking of membrane-associated proteins is not well understood. Here we show that TULP3 is required for transport of the atypical GTPase ARL13B into cilia, and for ciliary enrichment of ARL13B-dependent farnesylated and myristoylated proteins. ARL13B transport requires TULP3 binding to IFT-A core but not to phosphoinositides, unlike transmembrane cargo transport that requires binding to both by TULP3. A conserved lysine in TULP3's tubby domain mediates direct ARL13B binding and trafficking of lipidated and transmembrane cargoes. An N-terminal amphipathic helix in ARL13B flanking the palmitoylation site mediates binding to TULP3 and directs trafficking to cilia even in absence of palmitoylation and RVxP sorting motif. Therefore, TULP3 transports transmembrane proteins and ARL13B into cilia by capture of short sequences through a shared tubby domain site.

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Section: Introductionmentioning

confidence: 79%

Interactions between TULP3 tubby domain cargo site and ARL13B amphipathic helix promote lipidated protein transport to cilia

Palicharla

Hwang

Somatilaka

et al. 2021

Preprint

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“…Yet in the kidney, perinatal deletion of Thm1 causes cysts 20 , and deletion of Thm1 in juvenile Pkd2 cko mice affects cystogenesis in a tubular-dependent manner. Further, deletion of Thm1 in adult Pkd2 cko mice attenuates renal cystogenesis 42 . Thus, Thm1 influences cystogenesis in the kidney but not in the liver.…”

Section: Discussionmentioning

confidence: 98%

IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

Wang

Pottorf

Wang

et al. 2020

Preprint

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Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) genes in adult mouse models of ADPKD attenuates severity of PKD and PLD. Here we examine the role of deletion of IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knock-out mice. Perinatal deletion of Thm1 results in disorganized and expanded biliary regions, biliary fibrosis, shortened primary cilia on CK19+ biliary epithelial cells, and reduced Notch signaling. In contrast, perinatal deletion of Pkd2 causes PLD, with multiple CK19+ biliary epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knock-out mice increased hepatomegaly and liver necrosis, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 in adult mice, alone and together with Pkd2, did not cause a biliary phenotype nor affect Pkd2-mutant PLD, respectively. However, similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2-mutant cyst-lining cholangiocytes. Taken together, Thm1 is required for biliary tract development, likely by enabling Notch signaling, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not affect hepatic cystogenesis, suggesting divergent regulation of signaling and cystogenic processes in the liver by IFT-B and –A. Notably, increased Notch signaling in cyst-lining cholangiocytes may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target.

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Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner

Cited by 2 publications

References 82 publications

Interactions between TULP3 tubby domain cargo site and ARL13B amphipathic helix promote lipidated protein transport to cilia

Interactions between TULP3 tubby domain cargo site and ARL13B amphipathic helix promote lipidated protein transport to cilia

IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

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