Polycystins Recruit Cargo to Distinct Ciliary Extracellular Vesicle Subtypes

Overview

Journal bioRxiv

Date 2024 Apr 25

PMID 38659811

Authors

Inna A Nikonorova

Elizabeth desRanleau

Katherine C Jacobs

Joshua Saul

Jonathon D Walsh

Juan Wang

Maureen M Barr

Affiliations

Soon will be listed here.

Abstract

Therapeutic use of tiny extracellular vesicles (EVs) requires understanding cargo loading mechanisms. Here, we used a modular proximity label approach to identify EV cargo associated with the transient potential channel (TRP) polycystin PKD-2 of . Polycystins are conserved receptor-TRP channel proteins affecting cilium function; dysfunction causes polycystic kidney disease in humans and mating deficits in . Polycystin-2 EV localization is conserved from algae to humans, hinting at an ancient and unknown function. We discovered that polycystins associate with and direct specific cargo to EVs: channel-like PACL-1, dorsal and ventral membrane C-type lectins PAMLs, and conserved tumor necrosis-associated factor (TRAF) signaling adaptors TRF-1 and TRF-2. Loading of these components relied on polycystin-1 LOV-1. Our modular EV-TurboID approach can be applied in both cell- and tissue-specific manners to define the composition of distinct EV subtypes, addressing a major challenge of the EV field.

References

Yin Q, Lin S, Lamothe B, Lu M, Lo Y, Hura G . E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol. 2009; 16(6):658-66. PMC: 2834951. DOI: 10.1038/nsmb.1605. View

Mishra-Gorur K, Barak T, Kaulen L, Henegariu O, Jin S, Aguilera S . Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease. Proc Natl Acad Sci U S A. 2023; 120(16):e2214997120. PMC: 10120005. DOI: 10.1073/pnas.2214997120. View

Katsanis N . Ciliary proteins and exencephaly. Nat Genet. 2006; 38(2):135-6. DOI: 10.1038/ng0206-135. View

Park H . Structure of TRAF Family: Current Understanding of Receptor Recognition. Front Immunol. 2018; 9:1999. PMC: 6125299. DOI: 10.3389/fimmu.2018.01999. View

Jouret F, Devuyst O . Targeting chloride transport in autosomal dominant polycystic kidney disease. Cell Signal. 2020; 73:109703. DOI: 10.1016/j.cellsig.2020.109703. View

Ding H, Li L, Harris P, Yang J, Li X . Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease. Nat Commun. 2021; 12(1):4548. PMC: 8316472. DOI: 10.1038/s41467-021-24799-x. View

Fencl F, Janda J, Blahova K, Hribal Z, Stekrova J, Puchmajerova A . Genotype-phenotype correlation in children with autosomal dominant polycystic kidney disease. Pediatr Nephrol. 2009; 24(5):983-9. DOI: 10.1007/s00467-008-1090-9. View

Wyart C, Carbo-Tano M, Cantaut-Belarif Y, Orts-DelImmagine A, Bohm U . Cerebrospinal fluid-contacting neurons: multimodal cells with diverse roles in the CNS. Nat Rev Neurosci. 2023; 24(9):540-556. DOI: 10.1038/s41583-023-00723-8. View

Walsh J, Wang J, DeHart M, Nikonorova I, Srinivasan J, Barr M . Tracking N- and C-termini of C. elegans polycystin-1 reveals their distinct targeting requirements and functions in cilia and extracellular vesicles. PLoS Genet. 2022; 18(12):e1010560. PMC: 9829181. DOI: 10.1371/journal.pgen.1010560. View

10.

Orts-DelImmagine A, Cantaut-Belarif Y, Thouvenin O, Roussel J, Baskaran A, Langui D . Sensory Neurons Contacting the Cerebrospinal Fluid Require the Reissner Fiber to Detect Spinal Curvature In Vivo. Curr Biol. 2020; 30(5):827-839.e4. DOI: 10.1016/j.cub.2019.12.071. View

11.

Davis P, Zarowiecki M, Arnaboldi V, Becerra A, Cain S, Chan J . WormBase in 2022-data, processes, and tools for analyzing Caenorhabditis elegans. Genetics. 2022; 220(4). PMC: 8982018. DOI: 10.1093/genetics/iyac003. View

12.

Dokshin G, Ghanta K, Piscopo K, Mello C . Robust Genome Editing with Short Single-Stranded and Long, Partially Single-Stranded DNA Donors in . Genetics. 2018; 210(3):781-787. PMC: 6218216. DOI: 10.1534/genetics.118.301532. View

13.

Lomaga M, Henderson J, Elia A, Robertson J, Noyce R, Yeh W . Tumor necrosis factor receptor-associated factor 6 (TRAF6) deficiency results in exencephaly and is required for apoptosis within the developing CNS. J Neurosci. 2000; 20(19):7384-93. PMC: 6772765. View

14.

Wang J, Kaletsky R, Silva M, Williams A, Haas L, Androwski R . Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis. Curr Biol. 2015; 25(24):3232-8. PMC: 4698341. DOI: 10.1016/j.cub.2015.10.057. View

15.

Portman D, Emmons S . Identification of C. elegans sensory ray genes using whole-genome expression profiling. Dev Biol. 2004; 270(2):499-512. DOI: 10.1016/j.ydbio.2004.02.020. View

16.

Hogan M, Manganelli L, Woollard J, Masyuk A, Masyuk T, Tammachote R . Characterization of PKD protein-positive exosome-like vesicles. J Am Soc Nephrol. 2009; 20(2):278-88. PMC: 2637052. DOI: 10.1681/ASN.2008060564. View

17.

Lomaga M, Yeh W, Sarosi I, Duncan G, Furlonger C, Ho A . TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999; 13(8):1015-24. PMC: 316636. DOI: 10.1101/gad.13.8.1015. View

18.

Long H, Zhang F, Xu N, Liu G, Diener D, Rosenbaum J . Comparative Analysis of Ciliary Membranes and Ectosomes. Curr Biol. 2016; 26(24):3327-3335. PMC: 5173405. DOI: 10.1016/j.cub.2016.09.055. View

19.

Hilgendorf K, Myers B, Reiter J . Emerging mechanistic understanding of cilia function in cellular signalling. Nat Rev Mol Cell Biol. 2024; 25(7):555-573. PMC: 11199107. DOI: 10.1038/s41580-023-00698-5. View

20.

Das A, Middleton A, Padala P, Ledgerwood E, Mace P, Day C . The Structure and Ubiquitin Binding Properties of TRAF RING Heterodimers. J Mol Biol. 2021; 433(8):166844. DOI: 10.1016/j.jmb.2021.166844. View