Areas of Interests
- Research Interest
- Endo-lysosomes in immune and neuronal cell biology
Our immune system is orchestrated mainly by a variety of cell types derived via hematopoiesis. In addition to being essential for maintaining organismal health by fending off infectious microbes and viruses, a growing body of evidence is also revealing the role of immune cells in systemic interactions with various other cell types to modulate cellular and tissue homeostasis in different physiological contexts. To list a few examples, immune surveillance is constantly nipping cancerous cells in the bud after malignant mutation occurs during cell division; dysregulated immune cells initiate tissue/cellular damage in autoimmune diseases; phagocytic microglia prunes neuronal synapses to fine-tune synaptic transmission.
To understand the molecular mechanisms of how immune cells modulate different physiologies, it is best to model the interactions in a genetically tractable organism. To this end, we use Drosophila to uncover novel concepts, new genetic and molecular components that control how immune cells interact with other cells. We are particularly interested in studying the role of macrophages, the phagocytic immune cells that are often the first line of an immune response, in both normal physiological and pathological settings.
The major functions of macrophage are to “eat, digest, and release”. Phagocytosis (eat) allows uptake of extracellular materials for intracellular processing by the endo-lysosomal organelles (digest). Such processing is crucial to signal the cell how the immune response should be initiated (release), ranging from cytokine production, to phagocytosis regulation, and to antigen presentation. Our hypothesis is that endo-lysosomes are platforms for coordinating different signaling modules in immune cells.
One of the major determinants of endo-lysosomal function is ionic homeostasis. Therefore, a major focus of our research is to study how loss- or gain-of-function mutations of endo-lysosomal channels and transporters impact endo-lysosomal trafficking, biogenesis, and downstream signaling. In addition, by uncovering the upstream regulatory and downstream signaling pathways of these endo-lysosomal channels/transporters, we can simultaneously uncover the basic mechanisms of endo-lysosomal function , and also develop therapeutic concepts for treating diseases that involve endo-lysosomal dysfunction .
Neuronal and innate immune phenotypes are common in many lysosomal storage diseases, which result from endo-lysosomal dysfunction. The fact that Drosophila models of these diseases recapitulate pathological features of the diseases suggests that we can leverage the power of genetics to decipher the evolutionarily conserved roles of endo-lysosomes in a genetically tractable organism. We hope to leverage our findings in Drosophila to construct mechanistic models, and test the novel concepts on mammalian cells and animals.
Currently, our research is focused on:
- Studying how endo-lysosomes modulate signaling pathways in macrophage in response to microbes and damaged tissue
- The role of endo-lysosomal ionic homeostasis, which is regulated by evolutionarily conserved channels/transporters in genetic models of human disease
- Mechanism and functional outcome of the interactions between macrophages and the nervous system (neurons and glia) and metabolic organs (adipose tissue)
- Wong CO, Li R, Montell C, Venkatachalam K. (2012) Drosophila TRPML is required for TORC1 activation. Curr Biol. 22(17):1616-21.
- Wong CO, Palmieri M, Akhmedov D, Li J, Chao Y, Broadhead GT, Zhu MX, Collins C, Berdeaux R, Sardiello M, Venkatachalam K. (2015) Diminished MTORC1-Dependent JNK-Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction. Cell Reports. 12(12):2009-2020.
- Lau OC*, Shen B*, Wong CO*, Tjong YW, Lo CY, Wang HC, Huang Y, Yung WH, Chen YC, Fung ML, Rudd JA, Yao X. (2016). TRPC5 Channels Participate in Pressure-sensing in Aortic Baroreceptor. Nature Communications. (in press) * co-first-author.
- Wong CO, Palmieri M, Akhmedov D, Li J, Chao Y, Broadhead GT, Zhu MX, Collins C, Berdeaux R, Sardiello M, Venkatachalam K. (2015). Diminished MTORC1-Dependent JNK-Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction. Cell Reports. 12(12):2009-2020.
- Zhou Y, Wong CO, Cho KJ, van der Hoeven D, Liang H, Thakur DP, Luo J, Babic M, Zinsmaier KE, Zhu, MX, Hu H, Venkatachalam K, Hancock JF. (2015). SIGNAL TRANSDUCTION. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling. Science. 349(6250):873-6.
- Shen B*, Wong CO*#, Lau OC, Woo T, Bai S, Huang Y, Yao X#. (2015). Plasma Membrane Mechanical Stress Activates TRPC5 Channels. PLOS ONE. 10(4): e0122227. * co-first-author, # co-corresponding author
- Wong CO, Chen K, Lin YQ, Chao Y, Duraine L, Lu Z, Yoon WH, Sullivan JM, Broadhead GT, Sumner CJ, Lloyd TE, Macleod GT, Bellen HJ, Venkatachalam K. (2014). A TRPV Channel in Drosophila Motor Neurons Regulates Presynaptic Resting Ca2+ Levels, Synapse Growth, and Synaptic Transmission. Neuron. 84(4): 764-777. (cover article)
Comment in: Imler E and Zinsmaier KE (2014) TRPV1 Channels: Not So Inactive on the ER. Neuron. 84, 659-661.
- Feng X, Huang Y, Lu Y, Xiong J, Wong CO, Yang P, Xia J, Chen D, Du G, Venkatachalam K, Xia X, Zhu MX. (2014). Drosophila TRPML forms PI(3,5)P2-activated cation channels in both endolysosomes and plasma membrane. J Biol Chem. 289(7):4262-72.
- Wong CO, Li R, Montell C, Venkatachalam K. (2012). Drosophila TRPML is required for TORC1 activation. Curr Biol. 22(17):1616-21.
- Chan KH, Li T, Wong CO, Wong KB. (2012). Structural basis for GTP-dependent dimerization of hydrogenase maturation factor HypB. PLoS One. 7(1):e30547.
- Ma X, Cheng KT, Wong CO, O’Neil RG, Birnbaumer L, Ambudkar IS, Yao X. (2011). Heteromeric TRPV4-C1 channels contribute to store-operated Ca2+ entry in vascular endothelial cells. Cell Calcium. 50(6):502-9.
- Shen B, Kwan HY, Ma X, Wong CO, Du J, Huang Y, Yao X. (2011). cAMP activates TRPC6 channels via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mitogen-activated protein kinase kinase (MEK)-ERK1/2 signaling pathway. J Biol Chem. 286(22):19439-45.
- Wong CO*, Sukumar P*, Beech DJ, Yao X. (2010). Nitric oxide lacks direct effect on TRPC5 channels but suppresses endogenous TRPC5-containing channels in endothelial cells. Pflugers Arch. 460(1):121-30. * co-first-author
- Wong CO, Huang Y, Yao X. (2010). Genistein potentiates activity of the cation channel TRPC5 independently of tyrosine kinases. Br J Pharmacol. 159(7):1486-96.
- Ma X, Qiu S, Luo J, Ma Y, Ngai CY, Shen B, Wong CO, Huang Y, Yao X. (2010). Functional role of vanilloid transient receptor potential 4-canonical transient receptor potential 1 complex in flow-induced Ca2+ influx. Arterioscler Thromb Vasc Biol. 30(4):851-8.
- Chan CM, Tsoi H, Chan WM, Zhai S, Wong CO, Yao X, Chan WY, Tsui SK, Chan HY. (2009). The ion channel activity of the SARS-coronavirus 3a protein is linked to its pro-apoptotic function. Int J Biochem Cell Biol. 41(11):2232-9.
- Kwan HY, Wong CO, Chen ZY, Dominic Chan TW, Huang Y, Yao X. (2009). Stimulation of histamine H2 receptors activates TRPC3 channels through both phospholipase C and phospholipase D. Eur J Pharmacol. 602(2-3):181-7.
- Shen B, Cheng KT, Leung YK, Kwok YC, Kwan HY, Wong CO, Chen ZY, Huang Y, Yao X. (2008). Epinephrine-induced Ca2+ influx in vascular endothelial cells is mediated by CNGA2 channels. J Mol Cell Cardiol. 45(3):437-45.
- Cheng KT, Leung YK, Shen B, Kwok YC, Wong CO, Kwan HY, Man YB, Ma X, Huang Y, Yao X. (2008) CNGA2 channels mediate adenosine-induced Ca2+ influx in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 28(5):913-8.
Review Articles and Book Chapters
- Venkatachalam K, Wong CO, Zhu MX. (2014). The Role of TRPMLs in Endolysosomal Trafficking and Function. Cell Calcium. 58(1):48-56.
- Venkatachalam K, Wong CO, Montell C. (2013). Feast or famine: role of TRPML in preventing cellular amino acid starvation. Autophagy. 9(1):98-100. (cover article)
- Wong CO*, Yao X. (2011). TRP channels in vascular endothelial cells. Adv Exp Med Biol. 704:759-80. (* Corresponding author)
- Wong CO*, Yao X. (2008). Cyclic nucleotide-gated channels: a familiar channel family with a new function? Future Cardiol. 4(5):505-15. (* Corresponding author)