Yue Sun

All Publications

• Multiple regulators constrain the abundance of C. elegans DLK-1 in ciliated sensory neurons. G3 (Bethesda, Md.) Sun, Y., Zhou, J., Debnath, A., Xie, B., Wang, Z., Jin, Y. 2025

  Abstract

  The conserved MAP3K DLKs are widely known for their functions in synapse formation, axonal regeneration and degeneration, and neuronal survival, notably under traumatic injury and chronic disease conditions. In contrast, their roles in other neuronal compartments are much less explored. Through an unbiased forward genetic screening in C. elegans for altered patterns of GFP-tagged DLK-1 expressed from the endogenous locus, we have recently uncovered a mechanism by which the abundance of DLK-1 is tightly regulated by intraflagellar transport in ciliated sensory neurons. Here, we report additional mutants identified from the genetic screen. Most mutants exhibit increased accumulation of GFP::DLK-1 in sensory endings, and the levels of misaccumulated GFP::DLK-1 are exacerbated by loss of function in cebp-1, the b-Zip transcription factor acting downstream of DLK-1. We identify several new mutations in genes encoding proteins functioning in intraflagellar transport and cilia assembly, in components of BBSome, MAPK-15 and DYF-5 kinases. We report a novel mutation in the chaperone HSP90 that causes misaccumulation of GFP::DLK-1 and up-regulation of CEBP-1 selectively in ciliated sensory neurons. We also find that the guanylate cyclase ODR-1 constrains GFP::DLK-1 abundance throughout cilia and dendrites of AWC neurons. Moreover, in odr-1 mutants, AWC cilia display distorted morphology, which is ameliorated by loss of function in dlk-1 or cebp-1. These data expand the landscape of DLK-1 signaling in ciliated sensory neurons and underscore a high degree of cell- and neurite- specific regulation.

  View details for DOI 10.1093/g3journal/jkaf004

  View details for PubMedID 39854273

• An intraflagellar transport dependent negative feedback regulates the MAPKKK DLK-1 to protect cilia from degeneration. Proceedings of the National Academy of Sciences of the United States of America Sun, Y., Jin, Y. 2023; 120 (39): e2302801120

  Abstract

  Primary cilia are specialized organelles supporting the development and function of cells and organisms. Intraflagellar transport (IFT) is essential for cilia formation, maintenance, and function. In C. elegans ciliated sensory neurons, IFT interacts with signaling molecules to generate distinct morphological and function features and also to maintain the integrity of cilia. Here, we report an IFT-dependent feedback control on the conserved MAPKKK DLK-1 in the ciliated sensory neurons. DLK proteins are widely known to act in synapse formation, axon regeneration, and degeneration, but their roles in other neuronal compartments are understudied. By forward genetic screening for altered expression of the endogenously tagged DLK-1 we identified multiple ift mutants showing increased DLK-1 accumulation in the defective sensory endings. We show that in response to acute IFT disruption, DLK-1 accumulates rapidly and reversibly. The expression levels of the transcription factor CEBP-1, known to act downstream of DLK-1 in the development and maintenance of synapses and axons, are also increased in the ciliated sensory neurons of ift mutants. Interestingly, the regulation of CEBP-1 expression shows sensory neuron-type dependency on DLK-1. Moreover, in the sensory neuron AWC, which has elaborate cilia morphology, up-regulated CEBP-1 represses DLK-1 at the transcription level, thereby dampening DLK-1 accumulation. Last, the IFT-dependent regulatory loop of DLK-1 and CEBP-1 offers neuroprotection in a cilia degeneration model. These findings uncover a surveillance mechanism in which tight control on the DLK-1 signaling protects cilia integrity in a context-specific manner.

  View details for DOI 10.1073/pnas.2302801120

  View details for PubMedID 37722038

  View details for PubMedCentralID PMC10523469

• A tubulin-MAPKKK pathway engages tubulin isotype interaction for neuroprotection. Proceedings of the National Academy of Sciences of the United States of America Zhou, J., Feng, C., Sun, Y., Noma, K., Jin, Y. 2025; 122 (34): e2507208122

  Abstract

  The microtubule (MT) cytoskeleton is essential for neuronal morphology, neurite growth, synapse formation and maintenance, as well as regulation of signal transduction. Most cells express multiple isotypes of α- and β-tubulin that can coassemble into MTs. While a variety of signaling pathways regulate MT integrity and homeostasis, little is known about how tubulin isotypes interact in vivo. Here, we report a mechanism in which altered function of a neuronal β-tubulin in Caenorhabditis elegans activates the conserved kinase DLK-1 and its downstream signal transduction, which in turn upregulates expression of an α-tubulin isotype to ensure MT integrity. We find that alteration in the T7 loop of the β-tubulin/BEN-1 causes the formation of BEN-1-enriched islands along MTs in neurites. Combining genome editing with cellular imaging, we identified amino acid residues in α-tubulin/TBA-2 that are necessary for formation of BEN-1 islands. Activation of DLK-1 signaling in ben-1 mutants promotes TBA-2 transcription and protects axon and synapse morphology. These data uncover a positive feedback loop between DLK-1 and regulation of tubulin isotype interaction that maintains neuronal resilience.

  View details for DOI 10.1073/pnas.2507208122

  View details for PubMedID 40811477

• Loss of function in rpms-1 does not enhance phenotypes of rpm-1 mutants. microPublication biology Sun, Y., Gaio, D., Xie, B., Noma, K., Wu, Z., Jin, Y. 2024; 2024

  Abstract

  The C. elegans E3 ubiquitin ligase RPM-1 consists of 3,766 amino acids, with a RING finger domain at the C-terminus that functions to target the DLK-1 kinase for degradation for synapse development and axon termination. rpms-1 ( for rpm-1 short, aka F07B7.12 ) resides 35 kb away from rpm-1 on chromosome V, and is a near-perfect 12 kb duplication of rpm-1 , including the entire promoter region and coding sequences. RPMS-1 consists of 1,964 amino acids and is identical to the N-terminal half of RPM-1 , except the last 40 amino acids. Previous studies showed that transgenic overexpression of the duplicated region of rpm-1 (+) did not rescue synapse defects of rpm-1 loss of function mutants. Here, using CRISPR editing, we generated a double knockout of rpm-1 and rpms-1 . We find that axon and synapse defects in rpm-1rpms-1 double mutants resemble those in rpm-1 single mutants. Expression levels of endogenously tagged DLK-1 protein are increased to a comparable degree in rpm-1 and rpm-1rpms-1 mutants, compared to the control. These data, along with previous transgene expression analysis, support the idea that rpms-1 does not have a major role in RPM-1-mediated cellular processes.

  View details for DOI 10.17912/micropub.biology.001396

  View details for PubMedID 39712931

  View details for PubMedCentralID PMC11659880

• Coupled Control of Distal Axon Integrity and Somal Responses to Axonal Damage by the Palmitoyl Acyltransferase ZDHHC17. Cell reports Niu, J., Sanders, S. S., Jeong, H., Holland, S. M., Sun, Y., Collura, K. M., Hernandez, L. M., Huang, H., Hayden, M. R., Smith, G. M., Hu, Y., Jin, Y., Thomas, G. M. 2020; 33 (7): 108365

  Abstract

  After optic nerve crush (ONC), the cell bodies and distal axons of most retinal ganglion cells (RGCs) degenerate. RGC somal and distal axon degenerations were previously thought to be controlled by two parallel pathways, involving activation of the kinase dual leucine-zipper kinase (DLK) and loss of the axon survival factor nicotinamide mononucleotide adenylyltransferase-2 (NMNAT2), respectively. Here, we report that palmitoylation of both DLK and NMNAT2 by the palmitoyl acyltransferase ZDHHC17 couples these signals. ZDHHC17-dependent palmitoylation enables DLK-dependent somal degeneration after ONC and also ensures NMNAT-dependent distal axon integrity in healthy optic nerves. We provide evidence that ZDHHC17 also controls survival-versus-degeneration decisions in dorsal root ganglion (DRG) neurons, and we identify conserved motifs in NMNAT2 and DLK that govern their ZDHHC17-dependent regulation. These findings suggest that the control of somal and distal axon integrity should be considered as a single, holistic process, mediated by the concerted action of two palmitoylation-dependent pathways.

  View details for DOI 10.1016/j.celrep.2020.108365

  View details for PubMedID 33207199