Analysis of the N-terminal region of human MLKL, as well as two distinct MLKL isoforms, reveals new insights into necroptotic cell death

Arnez, Katja Hrovat, Kindlova, Michaela, Bokil, Nilesh J., Murphy, James M., Sweet, Matthew J. and Guncar, Gregor (2016) Analysis of the N-terminal region of human MLKL, as well as two distinct MLKL isoforms, reveals new insights into necroptotic cell death. Bioscience Reports, 36 1: . doi:10.1042/BSR20150246


Author Arnez, Katja Hrovat
Kindlova, Michaela
Bokil, Nilesh J.
Murphy, James M.
Sweet, Matthew J.
Guncar, Gregor
Title Analysis of the N-terminal region of human MLKL, as well as two distinct MLKL isoforms, reveals new insights into necroptotic cell death
Journal name Bioscience Reports   Check publisher's open access policy
ISSN 1573-4935
0144-8463
Publication date 2016-01-22
Sub-type Article (original research)
DOI 10.1042/BSR20150246
Open Access Status DOI
Volume 36
Issue 1
Total pages 7
Place of publication London, United Kingdom
Publisher Portland Press
Collection year 2017
Language eng
Abstract The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential effector of necroptotic cell death. Two distinct human MLKL isoforms have previously been reported, but their capacities to trigger cell death have not been compared directly. Herein, we examine these two MLKL isoforms, and further probe the features of the human MLKL N-terminal domain that are required for cell death. Expression in HEK293T cells of the N-terminal 201 amino acids (aa) of human MLKL is sufficient to cause cell death, whereas expression of the first 154 aa is not. Given that aa 1–125 are able to initiate necroptosis, our findings indicate that the helix that follows this region restrains necroptotic activity, which is again restored in longer constructs. Furthermore, MLKL isoform 2 (MLKL2), which lacks much of the regulatory pseudokinase domain, is a much more potent inducer of cell death than MLKL isoform 1 (MLKL1) in ectopic expression studies in HEK293T cells. Modelling predicts that a C-terminal helix constrains the activity of MLKL1, but not MLKL2. Although both isoforms are expressed by human monocyte-derived macrophages at the mRNA level, MLKL2 is expressed at much lower levels. We propose that it may have a regulatory role in controlling macrophage survival, either in the steady state or in response to specific stimuli.
Keyword Cell death
Isoform
Macrophage
Mixed lineage kinase domain-like
MLKL
Necroptosis
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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