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RIPK1 can function as an inhibitor rather than an initiator of RIPK3‐dependent necroptosis
Author(s) -
Kearney Conor J.,
Cullen Sean P.,
Clancy Danielle,
Martin Seamus J.
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13034
Subject(s) - necroptosis , ripk1 , programmed cell death , microbiology and biotechnology , kinase , tumor necrosis factor alpha , chemistry , biology , apoptosis , biochemistry , immunology
Tumour necrosis factor and lipopolysaccharide can promote a regulated form of necrosis, called necroptosis, upon inhibition of caspase activity in cells expressing receptor‐interacting serine/threonine kinase ( RIPK )3. Because inhibitors of RIPK 1 kinase activity such as necrostatin‐1 block necroptosis in many settings, RIPK 1 is thought to be required for activation of RIPK 3, leading to necroptosis. However, here we show that, although necrostatin potently inhibited tumour necrosis factor‐induced, lipopolysaccharide‐induced and poly IC ‐induced necroptosis, RIPK 1 knockdown unexpectedly potentiated this process. In contrast, RIPK 3 knockdown potently suppressed necroptosis under the same conditions. Significantly, necrostatin failed to block necroptosis in the absence of RIPK 1, indicating that its ability to suppress necroptosis was indeed RIPK 1‐dependent. These data argue that RIPK 1 is dispensable for necroptosis and can act as an inhibitor of this process. Our observations also suggest that necrostatin enhances the inhibitory effects of RIPK 1 on necroptosis, as opposed to blocking its participation in this process.