The non-specific lethal (NSL) complex regulates the expression of thousands of genes in both fruit flies and mammals. Abrogation of genes encoding for NSL components leads to the death of the organism, hence the complex’s curious name. Freiburg researchers found that the NSL complex acts as a “master” epigenetic regulator of genes that regulate the transport of molecules within the cilia of cells. In addition, these NSL-regulated genes are also vitally important for the function of kidney podocytes, a highly specialized cell type that does not carry cilia. These findings have important implications for ciliopathies and kidney disease.

Cilia are thin protrusions on the surface of cells. They have a wide variety of functions, including sensing of mechanical or chemical signals. Impaired cilia function plays a central role in the pathogenesis of many diseases. These so-called ciliopathies are associated with a wide range of symptoms, including hearing loss, visual impairment, obesity, kidney disease, and mental disability.

Within cilia, the intraciliary transport system delivers molecules between the cell body and the ciliary tip to ensure a constant supply of materials for cilia formation, maintenance and function. Mutations in genes encoding components of the intraciliary transport machinery could lead to ciliopathies. In their recent study in the journal Science Advances, a research team lead by Prof. Dr. Asifa Akhtar identified the NSL complex as a transcriptional regulator of genes known for their roles in the intraciliary transport system of cilia in different cell types. Akhtar is Director at the MPI of Immunobiology and Epigenetics in Freiburg, Honorary Professor at the University of Freiburg, and member of the Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies.

The NSL complex enables intraciliary transport

The NSL complex is a potent epigenetic modifier that regulates thousands of genes in fruit flies, mice, and humans. However, most of the functions of the NSL complex remain mysterious and have only recently begun to be elucidated. “Previous research from our lab indicates that the NSL complex controls many pathways critical for organismal development and cellular homeostasis,” says Akhtar.

The complex comprises several proteins and is a histone acetyltransferase (HAT) complex that prepares genes for activation. “Think of gene regulation as a team effort with different players. One important player is the NSL complex. It puts special marks on the histone proteins on which the DNA is wrapped around in the nucleus, like putting up green flags. These flags tell other regulators to switch on specific genes. We now found that the NSL complex does exactly this for a group of genes linked to moving materials within cilia,” says Tsz Hong Tsang, the first author of the study.

Cells need components of the NSL complex to build cilia

In the current study, the researchers used mouse cells to determine the functional consequences of loss of the NSL complex. They found that fibroblast cells lacking the NSL complex protein KANSL2 could not activate the transport genes or assemble cilia. “As cilia are the sensory and signaling hubs for cells, loss of KANSL2 leads to the inability of cells to activate the sonic hedgehog signaling pathway, which plays important roles in the regulation of embryonic development, cell differentiation, and maintenance of adult tissues as well as cancer,” says Akhtar.

NSL loss also affects non-ciliated cells

Impairment of the NSL complex also affected cells without cilia. “Interestingly, we found that podocytes also express intraciliary transport genes that are regulated by the NSL complex. So, we wondered what would happen if they are unable to switch on these genes,” says Tsang.

The researchers found that in non-ciliated mouse podocytes, special filtration cells in the kidney, the loss of KANSL2 leads to changes in microtubule dynamics in the cells. Microtubules are components of a cell’s skeleton and also important in intraciliary transport. While lacking cilia, mature podocytes have specialized cell processes called primary and secondary processes, whose functions rely heavily on components of the cell’s skeleton. Although apparently milder than the defect in ciliated cells, the Akhtar research group found that the cytoskeletal defects are likely the cause of severe glomerulopathy and kidney failure observed in mice lacking the NSL complex. This and other functions of intraciliary transport genes may help explain the complexity of symptoms presented by ciliopathies, which so far remain challenging for biological and clinical studies. The new insights into the role of the NSL complex could thus contribute to human health.

Original publication

Tsang TH, Wiese M, Helmstädter M, Stehle T, Seyfferth J, Shvedunova M, Holz H, Walz G, Akhtar A. Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells. In: Science Advances (2023). DOI: 10.1126/sciadv.adh5598

CIBSS profile of Prof. Dr. Asifa Akhtar

Original press release