Background Lysosomes play important roles in multiple aspects of physiology but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. was Stat6 a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes including hydrolases subunits of the vacuolar H+ Rabbit Polyclonal to SIRPB1. ATPase MK-0812 and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes Stat6 mediates only the activating effects of IL-4 by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4. Conclusions The current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation development and interferon signaling. Background Cells must be able to flexibly adjust the structural and functional capacity of their compartments in order to adapt to stress or changing nutrients to assume specialized tissue functions and to maintain homeostasis. The biogenesis of cellular organelles involves the assembly and targeting of numerous proteins and membrane lipids and often these processes are orchestrated by transcription factors whose activities are adjusted in response to stress or developmental cues. While much is known regarding the regulation of lipids mitochondria peroxisomes and the ER [1-6] understanding the transcriptional regulation of lysosomal function remains less advanced. Lysosomes are defined by acidic luminal pH characteristic membrane proteins and lipids MK-0812 and the presence of multiple acidic hydrolases that catalyze the degradation of material reaching the compartment through MK-0812 fluid-phase endocytosis phagocytosis or autophagy [7-10]. Abnormalities of lysosomal function content number morphology or gene expression are characteristic of multiple inherited lysosomal storage diseases of cellular senescence organismal ageing atherosclerosis Alzheimer’s and other neurodegenerative diseases [11-17]. Ectopic secretion of lysosomal proteases can lead to excessive extracellular matrix degradation which in turn contributes to metastasis emphysema atherosclerosis arthritis osteoporosis and the formation of aneurysms [14 18 Large-scale gene expression correlation analyses have shown that a number of lysosomal genes form coordinated clusters or synexpression groups suggesting that expression of these targets is co-regulated under varying conditions [21-23]. Sardiello et al. performed a pattern search of lysosomal promoters leading to the identification of a specific E-box which was found to be recognized by a basic helix-loop-helix transcription factor called TFEB [21 23 Ectopically expressed TFEB causes an upregulation of multiple lysosomal genes leading to increased numbers of lysosomes enhanced degradation of endocytic substrates and lysosomal exocytosis [21 24 Transcriptional regulation of lysosomal function has been studied mainly during autophagy and in this context several transcription factors have been shown to play roles in lysosomal gene regulation including GATA-1 [25] FoxO3 [25] and TFEB [26-29]. Lysosomal substrates of extracellular origin impose a particular load on macrophages and other phagocytic myeloid cells that process microbes senescent cells and effete tissue material [11 30 How the degradative capacity of lysosomes in such cells is regulated during stress and differentiation remains poorly understood. Here we used expression correlation analyses to search for novel regulators of lysosome-specific genes. We MK-0812 found that transcription factors whose expression correlates with lysosomal genes are often involved in differentiation embryonic development and interferon signaling. The strongest candidate that emerged MK-0812 from our computations was Signal Transducer and Activator of Transcription-6 (Stat6) a transcription factor regulated by IL-4 and IL-13. The roles of IL-4 and Stat6 in modulating lysosomal gene expression were evaluated in a primary cell culture model of alternatively activated mouse macrophages using data based on gene expression profiling.