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Full-Text Articles in Medicine and Health Sciences

Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak Mar 2019

Constitutive Interferon Signaling Maintains Critical Threshold Of Mlkl Expression To License Necroptosis, Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Chi G. Weindel, Irina Smirnova, Amy Y. Tang, Vladimir Ilyukha, Maxim Sorokin, Anton Buzdin, Katherine A. Fitzgerald, Alexander Poltorak

Katherine A. Fitzgerald

Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS/STING, and …


Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo Sep 2014

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Katherine A. Fitzgerald

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …


Nod2, Rip2 And Irf5 Play A Critical Role In The Type I Interferon Response To Mycobacterium Tuberculosis, Amit K. Pandey, Yibin Yang, Zhaozhao Jiang, Sarah M. Fortune, Francois Coulombe, Marcel A. Behr, Katherine A. Fitzgerald, Christopher M. Sassetti, Michelle A. Kelliher Jul 2011

Nod2, Rip2 And Irf5 Play A Critical Role In The Type I Interferon Response To Mycobacterium Tuberculosis, Amit K. Pandey, Yibin Yang, Zhaozhao Jiang, Sarah M. Fortune, Francois Coulombe, Marcel A. Behr, Katherine A. Fitzgerald, Christopher M. Sassetti, Michelle A. Kelliher

Katherine A. Fitzgerald

While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNalpha and IFNbeta, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds …