Susceptibility to Crohn's disease (CD), a complex inflammatory disease involving the small intestine, is controlled by up to 32 loci1. One CD risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG162. It is not known how Atg16L1 or autophagy contributes to intestinal biology or CD pathogenesis. To address these questions we generated and characterized mice that are hypomorphic for Atg16L1 protein expression, and validated conclusions based on studies in these mice by analyzing intestinal tissues that we collected from CD patients carrying the CD risk allele of ATG16L1. We show that Atg16L1 is a bona fide autophagy protein. Within the ileal epithelium, both Atg16L1 and a second essential autophagy protein Atg5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell which functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment3. Atg16L1 and Atg5-deficient Paneth cells exhibited striking abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to Atg16L1-deficient Paneth cells including increased expression of genes involved in PPAR signaling and lipid metabolism, acute phase reactants, as well as two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, CD patients homozygous for the ATG16L1 CD risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy protein-deficient mice and expressed increased levels of leptin protein. Thus, Atg16L1, and likely the process of autophagy, play their role within the intestinal epithelium of mice and CD patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.
T-bet is a member of the T-box family of transcription factors that appears to regulate lineage commitment in CD4 T helper (TH) lymphocytes in part by activating the hallmark TH1 cytokine, interferon-gamma (IFN-gamma). IFN-gamma is also produced by natural killer (NK) cells and most prominently by CD8 cytotoxic T cells, and is vital for the control of microbial pathogens. Although T-bet is expressed in all these cell types, it is required for control of IFN-gamma production in CD4 and NK cells, but not in CD8 cells. This difference is also apparent in the function of these cell subsets. Thus, the regulation of a single cytokine, IFN-gamma, is controlled by distinct transcriptional mechanisms within the T cell lineage.
The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.
Germinal centers (GC) are sites of intense B cell proliferation, central for T cell dependent antibody responses. However, the role of MYC, a key cell cycle regulator, in this process has been questioned. Here, we identified MYC positive B cell subpopulations in immature and mature GCs, and show through genetic ablation of Myc that they play indispensable roles in GC formation and maintenance. The identification of these functionally critical cellular subsets has important implications for human B cell lymphomagenesis, which mostly originates from GC B cells and frequently involves MYC chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the MYC positive GC subpopulations may be at a particularly high risk for malignant transformation.
V(D)J recombination and class switch recombination employ overlapping but distinct non-homologous end-joining (NHEJ) pathways to repair DNA double strand break (DSB) intermediates. 53BP1 is a DNA damage response protein that is rapidly recruited to sites of chromosomal DSBs, where it appears to function in a subset of ataxia-telangiectasia mutated (ATM) kinase, H2AX- and MDC1- dependent events1,2. A 53BP1 dependent end joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination CSR3, 4. Here, we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1 deficient lymphocytes distinct from that found in classical NHEJ-, H2AX-, MDC1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of un-repaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes bearing antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long range joining of DNA breaks.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.