USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis

Type 1 diabetes (T1D) is an autoimmune disease targeting pancreatic beta cells. Genome-wide association studies and gene expression analysis identified interferon (IFN)-driven gene networks as crucial pathways in the pathogenesis of T1D. IFNs are linked to the response to viral infections and might contribute to the initiation of the autoimmune process in T1D. We presently analyzed the role of ubiquitin-specific peptidase 18 (USP18), an interferon-stimulated gene 15-specific protease, on IFN-induced pancreatic beta cell inflammation and apoptosis. Our findings indicate that USP18 inhibition induces inflammation by increasing the STAT signaling and exacerbates IFN-induced beta cell apoptosis by the mitochondrial pathway of cell death. USP18 regulates activation of three BH3-only proteins, namely, DP5, Bim and PUMA in pancreatic beta cells, suggesting a direct link between regulators of the type I IFN signaling pathway and members of the BCL-2 family. USP18 depletion increases the expression of the T1D candidate gene MDA5, leading to an upregulation of double-stranded RNA-induced chemokine production. These data suggest a cross talk between the type I IFN signaling pathway and a candidate gene for T1D to increase pro-inflammatory responses in beta cells. The present study shows that USP18 is a key regulator of IFN signaling in beta cells and underlines the importance of this pathway in beta cell inflammation and death

A Small Ubiquitin-related Modifier-interacting Motif Functions as the Transcriptional Activation Domain of Krüppel-like Factor 4*

The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), regulates numerous biological processes, including proliferation, differentiation, and embryonic stem cell self-renewal. Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcription is not well defined. Small ubiquitin-related modifier (SUMO) is an important regulator of transcription. Here we show that KLF4 is both SUMOylated at a single lysine residue and physically interacts with SUMO-1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus. The SIM in KLF4 is required for transactivation of target promoters in a SUMO-1-dependent manner. Mutation of either the acidic or hydrophobic residues in the SIM significantly impairs the ability of KLF4 to interact with SUMO-1, activate transcription, and inhibit cell proliferation. Our study provides direct evidence that SIM in KLF4 functions as a transcriptional activation domain. A survey of transcription factor sequences reveals that established transactivation domains of many transcription factors contain sequences highly related to SIM. These results, therefore, illustrate a novel mechanism by which SUMO interaction modulates the activity of transcription factors

Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

The role of inflammation in insulitis and beta-cell loss in type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease with a strong inflammatory component. The latest studies indicate that innate immunity and inflammatory mediators have a much broader role in T1DM than initially assumed. Inflammation might contribute to early induction and amplification of the immune assault against pancreatic beta cells and, at later stages, to the stabilization and maintenance of insulitis. Inflammatory mediators probably contribute to the suppression of beta-cell function and subsequent apoptosis; they may also inhibit or stimulate beta-cell regeneration and might cause peripheral insulin resistance. The different effects of inflammation take place in different phases of the course of T1DM, and should be considered in the context of a 'dialog' between invading immune cells and the target beta cells. This dialog is mediated both by cytokines and chemokines that are released by beta cells and immune cells, and by putative, immunogenic signals that are delivered by dying beta cells. In this Review, we divided the role of inflammation in T1DM into three arbitrary stages: induction, amplification and maintenance or resolution of insulitis. These stages, and their progression or resolution, might depend on a patient's genetic background, which contributes to disease heterogeneity.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

Insights from AR gene mutations

The accumulation of somatic mutations on the background of natural germline variation is one of the fundamental mechanisms underpinning both disease and the development and progression of perhaps all tumors. For example, germline inactivating mutations in one allele of a tumor suppressor gene (TSG) (e.g., p53 or BRCA1) predisposes an individual to a lifetime of increased risk of cancer in particular tissues. In those cases, tumors commonly arise after somatic inactivation of the second TSG allele, and are often characterized by a younger age of onset and a more aggressive phenotype than tumors arising in the same tissues without a common or dominant genetic predisposition. A small proportion of prostate cancers do indeed occur in a hereditary manner, but it has been difficult to attribute inheritance and risk to a single gene. Even for the monoallelic androgen receptor (AR) gene on the X chromosome, which exhibits variously traits of an at-risk allele, oncogene, and mediator of prostate cancer progression and therapy resistance, inactivating germline variation in the AR is essentially nonexistent in this disease. Instead, germline AR variants often underpin the relatively common inherited syndrome of androgen insensitivity (AIS). In contrast, however, somatic variation of the AR is potentially a frequent event during tumor progression. As a consequence of these complexities, unraveling the precise role of the AR at each stage of prostate cancer progression, and indeed in different prostatic compartments or populations of tumor cells is challenging. In this chapter, we detail how the identification and characterization of somatic AR variants arising in prostate cancer has provided crucial information on (1) the role of the receptor throughout disease etiology and the emergence of castrate-recurrent disease, (2) the fine functional subdomain structure of the AR, (3) the oncogenic potential of aberrant AR signaling, and (4) new approaches to targeting AR function in disease management.Grant Buchanan, Eleanor F. Need, Tina Bianco-Miotto, Norman M. Greenberg, Howard I. Scher, Margaret M. Centenera, Lisa M. Butler, Diane M. Robins, and Wayne D. Tille