ICP6 Prevents RIP1 Activation to Hinder Necroptosis Signaling.

Hong Hu,Huayi Wang,Guoxiang Wu,Feiyang Yuan,Dandan Yu,Xiaoyan Liu,Zhaoqian Shu,Ning Nan

doi:10.3389/fcell.2020.595253

Abstract

Necroptosis is a type of programmed necrosis which depends on the activation of receptor-interacting protein kinase 3 (RIP3). Herpes simplex virus type 1 (HSV-1) is known to block necroptosis by the viral protein ICP6 in human cells, but its specific inhibitory mechanism is not fully understood. Here we reported that ICP6 could promote rather than suppress the formation of necrosome, the necroptosis signaling complex containing RIP3 and upstream regulator receptor-interacting protein kinase 1 (RIP1), but blocked RIP3 activation. Moreover, ICP6 could reduce the necroptosis-specific auto-phosphorylation of RIP1 regardless of the presence of RIP3. These results indicate that ICP6 block necroptosis through preventing RIP1 activation dependent signal transduction in necrosome.

Highlights

Under the selection pressure, the pathogen and the host are engaging in a long-term defense and counter-defense war (Mocarski et al, 2012; Mossman and Weller, 2015)
Since ICP6-RIP homotypic interaction motif (RHIM) is required for its function, confirmed by our data shown that RHIM-mutated ICP6 lost the ability to inhibit TSZ-induced necroptosis (Figures 1B,C), We proposed that receptor-interacting protein kinase 1 (RIP1)-receptor-interacting protein kinase 3 (RIP3) interactions maybe disturbed by ICP6-RHIM, so that it inhibited the necrosome formation and necroptosis signal transduction
In TNFinduced cell death pathways, the kinase activity is required for both RIP1 dependent apoptosis (RDA) and necroptosis (Yuan et al, 2019)

Summary

INTRODUCTION

The pathogen and the host are engaging in a long-term defense and counter-defense war (Mocarski et al, 2012; Mossman and Weller, 2015). TNF can induce cell necroptosis, a type of programmed necrosis when caspase-8 is inhibited (Vercammen et al, 1998). Necroptosis is regarded as an alternative defense pathway in the infected cells, when apoptosis is inhibited (Chan et al, 2015; Mossman and Weller, 2015). The inhibitory function of M45 in necroptosis pathway is solely dependent on its RHIM, which binds with RIP3-RHIM and form hetero-amyloids to prevent RIP3 activation by disturbing inter-filament assembly of RIP3-RHIM (Hu et al, 2020). ICP6 block necroptosis is not due to prevent RIP1-RIP3 binding and necrosome initiation. ICP6 can attenuate necroptosis signal induced auto-phosphorylation of RIP1 regardless of the presence of RIP3, suggesting ICP6 hinder necroptosis signaling through preventing RIP1 activation

MATERIALS AND METHODS

RESULTS

DATA AVAILABILITY STATEMENT