UNC-16 Interacts with LRK-1 and WDFY-3 to Regulate the Termination of Axon Growth

Overview

Journal Genetics

Publisher Oxford University Press

Specialty Genetics

Date 2024 Apr 6

PMID 38581414

Authors

Cody J Drozd

Tamjid A Chowdhury

Christopher C Quinn

Affiliations

Soon will be listed here.

Abstract

In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In Caenorhabditis elegans, the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1 (LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, 2 genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.

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References

Byrd D, Kawasaki M, Walcoff M, HISAMOTO N, Matsumoto K, Jin Y . UNC-16, a JNK-signaling scaffold protein, regulates vesicle transport in C. elegans. Neuron. 2001; 32(5):787-800. DOI: 10.1016/s0896-6273(01)00532-3. View

Feng Y, Press B, Wandinger-Ness A . Rab 7: an important regulator of late endocytic membrane traffic. J Cell Biol. 1995; 131(6 Pt 1):1435-52. PMC: 2120682. DOI: 10.1083/jcb.131.6.1435. View

Yim W, Mizushima N . Lysosome biology in autophagy. Cell Discov. 2020; 6:6. PMC: 7010707. DOI: 10.1038/s41421-020-0141-7. View

Sakamoto R, Byrd D, Brown H, Hisamoto N, Matsumoto K, Jin Y . The Caenorhabditis elegans UNC-14 RUN domain protein binds to the kinesin-1 and UNC-16 complex and regulates synaptic vesicle localization. Mol Biol Cell. 2004; 16(2):483-96. PMC: 545882. DOI: 10.1091/mbc.e04-07-0553. View

Noma K, Goncharov A, Ellisman M, Jin Y . Microtubule-dependent ribosome localization in neurons. Elife. 2017; 6. PMC: 5577916. DOI: 10.7554/eLife.26376. View

Brown H, Van Epps H, Goncharov A, Grant B, Jin Y . The JIP3 scaffold protein UNC-16 regulates RAB-5 dependent membrane trafficking at C. elegans synapses. Dev Neurobiol. 2008; 69(2-3):174-90. PMC: 2707823. DOI: 10.1002/dneu.20690. View

Reck-Peterson S, Redwine W, Vale R, Carter A . The cytoplasmic dynein transport machinery and its many cargoes. Nat Rev Mol Cell Biol. 2018; 19(6):382-398. PMC: 6457270. DOI: 10.1038/s41580-018-0004-3. View

Hill S, Kauffman K, Krout M, Richmond J, Melia T, Colon-Ramos D . Maturation and Clearance of Autophagosomes in Neurons Depends on a Specific Cysteine Protease Isoform, ATG-4.2. Dev Cell. 2019; 49(2):251-266.e8. PMC: 6482087. DOI: 10.1016/j.devcel.2019.02.013. View

Platzer K, Sticht H, Edwards S, Allen W, Angione K, Bonati M . De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. Am J Hum Genet. 2019; 104(2):203-212. PMC: 6369540. DOI: 10.1016/j.ajhg.2018.12.008. View

10.

Singh K, Lau C, Manigrasso G, Gama J, Gassmann R, Carter A . Molecular mechanism of dynein-dynactin complex assembly by LIS1. Science. 2024; 383(6690):eadk8544. PMC: 7615804. DOI: 10.1126/science.adk8544. View

11.

Drozd C, Quinn C . UNC-116 and UNC-16 function with the NEKL-3 kinase to promote axon targeting. Development. 2023; 150(18). PMC: 10561693. DOI: 10.1242/dev.201654. View

12.

Edwards S, Yu S, Hoover C, Phillips B, Richmond J, Miller K . An organelle gatekeeper function for Caenorhabditis elegans UNC-16 (JIP3) at the axon initial segment. Genetics. 2013; 194(1):143-61. PMC: 3632462. DOI: 10.1534/genetics.112.147348. View

13.

Celestino R, Gama J, Castro-Rodrigues A, Barbosa D, Rocha H, dAmico E . JIP3 interacts with dynein and kinesin-1 to regulate bidirectional organelle transport. J Cell Biol. 2022; 221(8). PMC: 9284427. DOI: 10.1083/jcb.202110057. View

14.

Tooze S, Abada A, Elazar Z . Endocytosis and autophagy: exploitation or cooperation?. Cold Spring Harb Perspect Biol. 2014; 6(5):a018358. PMC: 3996471. DOI: 10.1101/cshperspect.a018358. View

15.

Onishi K, Tian R, Feng B, Liu Y, Wang J, Li Y . LRRK2 mediates axon development by regulating Frizzled3 phosphorylation and growth cone-growth cone communication. Proc Natl Acad Sci U S A. 2020; 117(30):18037-18048. PMC: 7395514. DOI: 10.1073/pnas.1921878117. View

16.

Choudhary B, Kamak M, Ratnakaran N, Kumar J, Awasthi A, Li C . UNC-16/JIP3 regulates early events in synaptic vesicle protein trafficking via LRK-1/LRRK2 and AP complexes. PLoS Genet. 2017; 13(11):e1007100. PMC: 5716593. DOI: 10.1371/journal.pgen.1007100. View

17.

Montagnac G, Sibarita J, Loubery S, Daviet L, Romao M, Raposo G . ARF6 Interacts with JIP4 to control a motor switch mechanism regulating endosome traffic in cytokinesis. Curr Biol. 2009; 19(3):184-95. DOI: 10.1016/j.cub.2008.12.043. View

18.

Arimoto M, Koushika S, Choudhary B, Li C, Matsumoto K, Hisamoto N . The Caenorhabditis elegans JIP3 protein UNC-16 functions as an adaptor to link kinesin-1 with cytoplasmic dynein. J Neurosci. 2011; 31(6):2216-24. PMC: 6633058. DOI: 10.1523/JNEUROSCI.2653-10.2011. View

19.

Biskup S, Moore D, Celsi F, Higashi S, West A, Andrabi S . Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol. 2006; 60(5):557-569. DOI: 10.1002/ana.21019. View

20.

Alegre-Abarrategui J, Christian H, Lufino M, Mutihac R, Venda L, Ansorge O . LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet. 2009; 18(21):4022-34. PMC: 2758136. DOI: 10.1093/hmg/ddp346. View