Constitutive Interferon Signaling Maintains Critical Threshold of MLKL Expression to License Necroptosis

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2018 May 23

PMID 29786074

Citations 90

Authors

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

Affiliations

Soon will be listed here.

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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