Understanding the Role of the NSL Complex in Ciliopathies and Kidney Disease
Introduction
The non-specific lethal (NSL) complex is a chromatin-associated factor that has been shown to regulate the expression of thousands of genes in both fruit flies and mammals. Knockout of the NSL genes leads to the death of the organism, and this phenotype gives rise to the curious name of this complex. The Max Planck researchers have now identified the NSL complex as a “master” epigenetic regulator of intraciliary transport genes in multiple cell types and species. This discovery has important implications for ciliopathies and kidney disease.
The Significance of Cilia
Cilia are thin, eyelash-like extensions on the surface of cells that perform a wide variety of functions. They act as mechanosensors or chemosensors, playing crucial roles in many signaling pathways. In recent decades, cilia have emerged as central players in the pathogenesis of ciliopathies. These diseases are associated with a wide range of symptoms, including hearing loss, visual impairment, obesity, kidney disease, and mental disability. Different genetic mutations affecting the formation, maintenance, and function of cilia can lead to the development of ciliopathies.
The Role of Intraciliary Transport
The proper assembly, maintenance, and function of cilia depend on a process called “intraciliary transport.” This process involves the movement of cargo between the cell body and the ciliary tip to ensure a constant supply of materials. Mutation of genes that encode components within the intraciliary transport machinery can lead to ciliopathies. In a recent study published in the journal Scientific Advances, Asifa Akhtar’s lab at the Max Planck Institute identified the NSL complex as a transcriptional regulator of genes involved in the intraciliary transport system across multiple cell types.
Unraveling the Functions of the NSL Complex
The NSL complex is a potent epigenetic modifier that regulates thousands of genes in fruit flies, mice, and humans. However, its exact functions have remained a mystery until recently. Previous research from Asifa Akhtar’s laboratory indicates that the NSL complex controls critical pathways for organism development and cellular homeostasis. The complex comprises several proteins and acts as a histone acetyltransferase (HAT) complex, priming genes for activation. By placing special marks on the histone proteins that DNA wraps around in the nucleus, the NSL complex activates specific genes. In the recent study, the NSL complex was found to play a crucial role in regulating a group of genes associated with intraciliary transport.
The Role of the NSL Complex in Cilia Formation
The intraciliary transport system is essential for the proper formation of functional cilia. This transportation system allows the cell to move material from the base of the cilium to the growing tip, similar to building a tower. In the study conducted by Akhtar’s lab, they used mouse cells to investigate the consequences of losing the NSL complex. The researchers found that fibroblasts lacking the NSL complex protein KANSL2 were unable to activate transport genes or assemble cilia. This deficiency in cilia formation had profound effects on cellular processes, such as the hedgehog sonic signaling pathway, which plays important roles in regulating embryonic development, cell differentiation, and the maintenance of adult tissues. Loss of the NSL complex’s components prevents cells from fulfilling their sensory and signaling functions, leading to various pathological conditions.
Expanding Beyond Ciliated Cells
Cilia are found on most types of cells in the human body, explaining why ciliopathies can affect different organs and tissues. However, there are also cells that do not possess cilia, such as mature glomerular podocytes in the kidney. Surprisingly, the researchers discovered that podocytes express intraciliary transport genes regulated by the NSL complex, even though they lack cilia. This raises the question of what would happen if these genes were not activated in non-ciliated cells. The study found that in non-ciliated mouse podocytes, the loss of KANSL2 leads to changes in microtubule dynamics, essential components of the cytoskeleton responsible for the mechanical stabilization of the cell and intracellular transport between different organelles. Although the defects observed in podocytes were milder compared to hair cells, the cytoskeletal abnormalities were found to be the likely cause of severe glomerulopathy and kidney failure in mice lacking the NSL complex. These findings highlight the importance of intraciliary transport genes beyond their role in cilia and provide insights into the complexity of ciliopathy symptoms.
Implications for Ciliopathies and Kidney Disease
Ciliopathies affecting organs such as the kidney, liver, eye, ear, and central nervous system pose significant challenges for both biologists and clinicians. By identifying the NSL complex as a critical regulator of intraciliary transport genes, the researchers at the Max Planck Institute hope to shed light on the underlying mechanisms of these diseases. Understanding the regulation of cilia-related organelles and associated genes can potentially lead to new therapeutic strategies for ciliopathies and kidney diseases. The study of the NSL complex’s role in intraciliary transport not only contributes to our knowledge of cellular processes but also holds promise for improving human health.
Conclusion
The discovery of the NSL complex as a “master” epigenetic regulator of intraciliary transport genes has provided valuable insights into the mechanisms underlying ciliopathies and kidney disease. The NSL complex’s role in activating transport genes and ensuring proper cilia formation highlights its importance in cellular processes and development. Furthermore, the identification of NSL-regulated intraciliary transport genes in non-ciliated cells like podocytes expands our understanding of the complex interplay between different cellular components. These findings pave the way for further research and potential therapeutic interventions for ciliopathies and related disorders.
Summary
Researchers at the Max Planck Institute have identified the non-specific lethal (NSL) complex as a crucial regulator of intraciliary transport genes. The NSL complex, a chromatin-associated factor, plays a significant role in the expression of thousands of genes in fruit flies, mice, and humans. Knockout of the NSL genes leads to organism death, underscoring the importance of this complex. The recent study conducted by Asifa Akhtar’s lab revealed that the NSL complex acts as a “master” epigenetic regulator of genes involved in the intraciliary transport system across various cell types.
This research has important implications for understanding ciliopathies, a group of diseases associated with defects in cilia formation and function. Cilia are thin extensions found on the surface of cells that perform essential functions in mechanosensing, signaling, and various biological processes. Mutations affecting the genes responsible for cilia structure and intraciliary transport can lead to a wide range of symptoms, including hearing loss, visual impairment, obesity, kidney disease, and mental disability.
Intraciliary transport is crucial for the proper assembly, maintenance, and function of cilia. It involves the movement of cargo between the cell body and the ciliary tip, ensuring a constant supply of materials. The NSL complex was found to be a transcriptional regulator of intraciliary transport genes, regardless of whether or not a specific cell has cilia. This discovery expands our understanding of cilia-related processes and their broader implications.
The NSL complex, composed of several proteins, acts as a histone acetyltransferase (HAT) complex, priming genes for activation. By placing specific marks on the histone proteins around which DNA wraps, the NSL complex activates genes associated with intraciliary transport. The loss of components within the NSL complex, such as the protein KANSL2, has been shown to prevent the activation of transport genes and hinder cilia formation in cell types like fibroblasts. This deficiency in cilia assembly affects cellular processes, including critical signaling pathways like the hedgehog sonic pathway.
Interestingly, the researchers also found that non-ciliated cells, such as mature glomerular podocytes in the kidney, express intraciliary transport genes regulated by the NSL complex. Although these cells lack cilia, the loss of the NSL complex leads to changes in microtubule dynamics, essential components of the cytoskeleton that stabilize the cell and facilitate intracellular transport. These disruptions in cytoskeletal components have been linked to severe glomerulopathy and kidney failure. This discovery highlights the intricate connections and multifaceted roles of intraciliary transport genes beyond their association with cilia.
The identification of the NSL complex as a critical regulator of intraciliary transport genes opens up new avenues for understanding and potentially treating ciliopathies and kidney diseases. By unraveling the mechanisms underlying cilia-related diseases and the genes associated with them, researchers hope to develop targeted therapeutic strategies. These findings not only enhance our knowledge of cellular processes but also contribute to the broader goal of improving human health.
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The non-specific lethal (NSL) complex is a chromatin-associated factor that has been shown to regulate the expression of thousands of genes in both fruit flies and mammals. Knockout of the NSL genes leads to the death of the organism, and this phenotype gives rise to the curious name of this complex. The Max Planck researchers have now identified the NSL complex as a “master” epigenetic regulator of intraciliary transport genes in multiple cell types and species. The study reveals that this class of genes is “turned on” by the NSL complex regardless of whether or not a particular cell has cilia. Furthermore, the researchers discovered that this class of cilia-associated genes is in fact vitally important for the function of renal podocytes, a highly specialized cell type that, paradoxically, does not bear cilia. These findings have important implications for ciliopathies and kidney disease.
Cilia are thin, eyelash-like extensions on the surface of cells. They perform a wide variety of functions, acting as mechanosensors or chemosensors, and play crucial roles in many signaling pathways. In recent decades, the organelle has undergone a remarkable, yet sinister career transformation. It evolved from an organelle whose relevance was unclear to become a central player in the pathogenesis of a large group of diseases. These so-called ciliopathies are associated with a wide range of symptoms, including hearing loss, visual impairment, obesity, kidney disease, and mental disability. Different genetic mutations affect the formation, maintenance, and function of cilia, resulting in these ciliopathies, which can sometimes be multi-organ syndromic disorders.
The proper assembly, maintenance, and function of cilia depend on a process called “intraciliary transport.” Components of the intraciliary transport system “walk” on microtubules to deliver cargo between the cell body and the ciliary tip to ensure a constant supply of materials. Mutation of genes that encode components within the intraciliary transport machinery could cause ciliopathies. In the recent study of him in the journal Scientific advancesAsifa Akhtar’s lab identified the NSL complex as a transcriptional regulator of genes known for their role in the intraciliary transport system of cilia across multiple cell types.
The NSL complex allows 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 a mystery and have only recently begun to be elucidated. “Previous research from our laboratory indicates that the NSL complex controls many critical pathways for organism development and cellular homeostasis,” says Asifa Akhtar, Director of the MPI for Immunobiology and Epigenetics in Freiburg.
The complex comprises several proteins and is a histone acetyltransferase (HAT) complex that primes genes for activation. “Think of gene regulation as a team effort with different players. One major player is the NSL complex. It places special marks on the histone proteins that DNA wraps around in the nucleus, much like putting up green flags. These flags they tell other regulators to activate specific genes. We have now discovered that the NSL complex does exactly this for a group of genes linked to moving materials within the cilia,” says Tsz Hong Tsang, the study’s first author.
Without components of the NSL complex, the cell cannot form a cilium.
The intraciliary transport system is essential because it is necessary to build a functional cilium. The cell uses the intraciliary transport system to move material from the base of the cilium to the growing tip, similar to building a tower. In the study, the researchers used mouse cells to determine the functional consequences of the loss of the NSL complex in the cells.
They found that fibroblasts lacking the NSL complex protein KANSL2 could not activate transport genes or assemble cilia. “As cilia are the sensory and signaling centers of cells, loss of KANSL2 leads to the inability of cells to activate the hedgehog sonic signaling pathway, which plays important roles in regulating embryonic development, cell differentiation and maintenance of adult tissues as well, such as cancer,” says Asifa Akhtar.
Although they are tiny nubs, these sensory organelles are incredibly important to cells. Ciliopathies, which affect organs as diverse as the kidney, liver, eye, ear, and central nervous system, remain a challenge for biological and clinical studies. The researchers at the Max Planck Institute in Freiburg hope that their analysis of the role of the NSL complex has provided important information about the regulation of these organelles and the genes associated with them, thus contributing to human health.
Consequences of the loss of NSL in non-hair cells
Cilia are found on most types of cells in the human body. This explains why ciliopathies can affect so many different organs and tissues, but there are also cells that are not ciliated. One of the types of cells that do not have cilia are mature glomerular podocytes, which are special filter cells in the kidney. “Interestingly, we found that podocytes also express these intraciliary transport genes that are regulated by the NSL complex. So, we wondered what would happen if they couldn’t activate these genes,” says Tsz Hong Tsang.
The researchers found that in non-ciliated mouse podocytes, the loss of KANSL2 causes changes in microtubule dynamics in the cells. Microtubules are components of the cytoskeleton responsible for the mechanical stabilization of the cell and intracellular transport between different organelles. Although they lack cilia, mature podocytes have specialized cellular processes that extend from the cell body called primary and secondary processes, the functions of which are highly dependent on cytoskeletal components. Although apparently milder than the hair cell defect, Akhtar’s lab found that the cytoskeletal defects are likely the cause of the severe glomerulopathy and kidney failure seen in mice lacking the NSL complex. These and other extraciliary functions of intraciliary transport genes may help explain the complexity of the symptoms of ciliopathies.
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