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Viral M45 and necroptosis‐associated proteins form heteromeric amyloid assemblies
Author(s) -
Pham Chi LL,
Shanmugam Nirukshan,
Strange Merryn,
O'Carroll Ailis,
Brown James WP,
Sierecki Emma,
Gambin Yann,
Steain Megan,
Sunde Margaret
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201846518
Subject(s) - necroptosis , microbiology and biotechnology , biology , amyloid (mycology) , virology , programmed cell death , genetics , apoptosis , botany
The murine cytomegalovirus protein M45 protects infected mouse cells from necroptotic death and, when heterologously expressed, can protect human cells from necroptosis induced by tumour necrosis factor receptor ( TNFR ) activation. Here, we show that the N‐terminal 90 residues of the M45 protein, which contain a RIP homotypic interaction motif ( RHIM ), are sufficient to confer protection against TNFR ‐induced necroptosis. This N‐terminal region of M45 drives rapid self‐assembly into homo‐oligomeric amyloid fibrils and interacts with the RHIM s of the human kinases RIPK 1 and RIPK 3, and the Z‐ DNA binding protein 1 ( ZBP 1), to form heteromeric amyloid fibrils in vitro . Mutation of the tetrad residues in the M45 RHIM attenuates homo‐ and hetero‐amyloid assembly by M45, suggesting that the amyloidogenic nature of the M45 RHIM underlies its biological activity. The M45 RHIM preferentially interacts with RIPK 3 and ZBP 1 over RIPK 1 and alters the properties of the host RHIM protein assemblies. Our results indicate that M45 mimics the interactions made by RIPK 1 or ZBP 1 with RIPK 3, thereby forming heteromeric amyloid structures, which may explain its ability to inhibit necroptosis.