NDR1 and NDR2 are kinases in the large tumor suppressor subfamily, in the Hippo signaling pathway. Nuclear Dbf2-related (NDR) kinases are important in several cellular processes but have also been shown to have a significant role in regulating infection and inflammation.
Image Credit: https://www.frontiersin.org/articles/10.3389/fimmu.2020.00534/full
The basics of NDR1 and NDR2
NDR1 and 2 are also sometimes called serine/threonine kinase 38 (STK38) and serine/threonine kinase 38 like (STK38L), respectively. They belong to a family of kinases that are highly conserved in all eukaryotes, all the way from yeasts to humans. This family of kinases is the NDR/LATS kinase family, within the AGC group of kinases.
NDR1 is mainly distributed in the nucleus of the cell, whereas NDR2 is located in the cytoplasm. They are both involved in morphological changes, duplication of the centrosome, cell cycle, and apoptosis. Some studies also implicate NDR1 and 2 in embryonic development, neurodevelopment, and cancer biology. Lastly, NDR1 and 2 are increasingly implicated in infection.
NDR in innate immunity
The innate immune system is the body’s first line of defense against pathogens. Toll-like receptors bind ligands that signal cellular damage. Some evidence shows that NDR1 can negatively regulate the immune response that is mediated by Toll-like receptor 9 in macrophages. Specifically, NDR1 binds with a ubiquitin ligase, which in turn leads to disruption of the pathway that produces TNF-α and IL-6. Therefore, a deficiency in NDR1 can lead to increases in pro-inflammatory cytokines.
NDR2 is believed to have a similar role to NDR1. Decreasing NDR2 leads to an increase in interleukin secretion. However, it is NDR1 that is primarily believed to be involved in preventing excessive production of inflammatory cytokines, and as such, it is critical in protecting the host from inflammation induced by toll-like receptor 9.
NDR in regulating inflammation
In addition to their role in the innate immune system, NDR1 and 2 have been implicated in inflammatory responses. NDR1 can interact with components in the NF-kB signaling pathway, to positively regulate inflammation. Similarly, NDR1 can bind competitively to TRAF3, and as such, it functions as a positive regulator of IL-17 signal transduction to facilitate inflammation.
On the other hand, some evidence indicates that NDR2 inhibits IL-17 signaling. It does so by facilitating the breakdown of signaling molecules. The effect is that NDR2 minimized inflammation triggered by IL-17, in direct opposition to the behavior by NDR1. In addition to the role of these inflammatory pathways in infection, they are also implicated in autoimmune diseases. Therefore, NDR1 and 2 have been hypothesized as potential drug targets for autoimmune diseases like multiple sclerosis.
NDR in diseases
NDR 1 and 2 are indicated to be involved in the body’s antiviral response by positively regulating the antiviral immune response induced by retinoic acid-inducible gene I. There is some evidence that NDR1 and 2 kinases have been incorporated into HIV-1 particles. These are also implicated in the pathogenicity of HIV-1, as NDR1 and 2 can be cleaved by the HIV protease and therefore inhibit their activity.
NDR1 and 2 have also been shown to work in a protective capacity for other diseases. NDR1 can phosphorylate Yes-associated proteins and can therefore act as a tumor suppressor in colorectal cancer. Furthermore, NDR1 is involved in replication by positively regulating centrosome duplication. Therefore, NDR1 and 2 have varied roles in the animal immune system, ranging from normal cellular function to protect the host from pathogenic infections and inflammation.
NDR1 and 2 can be involved in both plant and animal diseases, in addition to their role in general immunity and inflammation. In plants, the resistance to bacterial and fungal pathogens is mediated by plant disease resistance (R) genes. However, this also requires the NDR1 gene. Therefore, NDR genes are intrinsically tied to the immune response against diseases in both plants and animals.
Plants that are deficient in NDR1 show increased growth of populations of pathogens. Specifically, NDR1 is essential for resistance to bacterial and fungal pathogens. Mutations of NDR1 increases the susceptibility of plants to strains of Pseudomonas syringae bacteria and Peronospora parasitica fungi.
- Ye, X., Ong, N., An, H. and Zheng, Y., 2020. The Emerging Roles of NDR1/2 in Infection and Inflammation. Frontiers in Immunology, 11 (534).
- Century, K., Shapiro, A., Repetti, P., Dahlbeck, D., Holub, E. and Staskawicz, B., 1997. NDR1, a Pathogen-Induced Component Required for Arabidopsis Disease Resistance. Science, 278 (5345), pp. 1963-1965.
- Knepper, C., Savory, E., and Day, B., 2011. The role of NDR1 in pathogen perception and plant defense signaling. Plant Signaling & Behavior, 6(8), pp. 1114-1116.
- Ma, C., Lin, W., Liu, Z., Tang, W., Gautam, R., Li, H., Qian, Y., Huang, H., and Wang, X., 2017. NDR1 protein kinase promotes IL‐17 and TNF‐α mediated inflammation by competitively binding TRAF 3. EMBO reports 18(4), pp. 586-602.