Abstract
Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation.
Highlights
Mixed-lineage kinase domain-like protein (MLKL) is the terminal executor of necroptosis, a form of programmed necrotic cell death, and is controlled by RIPK3 downstream of TNFR activated RIPK1 or TLR3 activated TRIF signaling cascades[1,2]
RNA-seq analysis of Human umbilical vein endothelial cells (HUVEC) demonstrated that MLKL and RIPK1 were highly expressed in HUVEC, whereas RIPK3 was lowly expressed (Fig. 1a)
Real-time PCR analysis demonstrated a similar result (Supplementary Fig. S1A). Comparison of their expression in HUVEC and HT-29, a human colorectal carcinoma cell line, revealed that RIPK1 and MLKL were expressed in HUVEC and HT29, while RIPK3 was normally expressed in HT29 but at an extremely low level in HUVEC (Fig. 1b, c)
Summary
Mixed-lineage kinase domain-like protein (MLKL) is the terminal executor of necroptosis, a form of programmed necrotic cell death, and is controlled by RIPK3 downstream of TNFR activated RIPK1 or TLR3 activated TRIF signaling cascades[1,2]. RIPK3 phosphorylates T357/S358 within the activation loop of MLKL, which leads to a conformational change in MLKL, exposing the N-terminal membrane-disrupting 4-helix bundle domain[1,3,4]. MLKL is further phosphorylated by TAM kinase at Y376 to initiate oligomerization[5]. Oligomerized MLKL inserts its N-terminal into the plasma membrane and induces necroptotic cell death[6,7,8]. Recent studies demonstrated that MLKL could exert non-necroptotic functions[9,10,11,12,13,14].
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