Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis
Sarhan, Joseph ; Liu, Beiyun C. ; Muendlein, Hayley I. ; Weindel, Chi G. ; Smirnova, Irina ; Tang, Amy Y. ; Ilyukha, Vladimir ; Sorokin, Maxim ; Buzdin, Anton ; Fitzgerald, Katherine A ... show 1 more
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Abstract
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 maintains the expression of MLKL and one or more unknown effectors above a critical threshold to allow for MLKL oligomerization and cell death. Finally, we found that elevated IFN-signaling in systemic lupus erythematosus (SLE) augments necroptosis, providing a link between pathological IFN and tissue damage during autoimmunity.
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Cell Death Differ. 2019 Jan;26(2):332-347. doi: 10.1038/s41418-018-0122-7. Epub 2018 May 21. Link to article on publisher's site