Abstract
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death. Dovey et al. report an unexpected layer of regulation governing a form of cell death termed necroptosis. They find that the inositol phosphate code controls the executioner protein MLKL to induce cell lysis. This study deepens our understanding of cell death mechanisms important for infection, inflammation, and cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 936-948.e7 |
| Journal | Molecular Cell |
| Volume | 70 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jun 7 2018 |
Fingerprint
Keywords
- cell death
- inositol phosphate
- IP kinase
- IPMK
- ITPK1
- MLKL
- necroptosis
- proinflammatory cytokine
- regulated necrosis
- RIPK3
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
MLKL Requires the Inositol Phosphate Code to Execute Necroptosis. / Dovey, Cole M.; Diep, Jonathan; Clarke, Bradley P.; Hale, Andrew T.; McNamara, Dan E.; Guo, Hongyan; Brown, Nathaniel W.; Cao, Jennifer Yinuo; Grace, Christy R.; Gough, Peter J.; Bertin, John; Dixon, Scott J.; Fiedler, Dorothea; Mocarski, Edward S.; Kaiser, William; Moldoveanu, Tudor; York, John D.; Carette, Jan E.
In: Molecular Cell, Vol. 70, No. 5, 07.06.2018, p. 936-948.e7.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MLKL Requires the Inositol Phosphate Code to Execute Necroptosis
AU - Dovey, Cole M.
AU - Diep, Jonathan
AU - Clarke, Bradley P.
AU - Hale, Andrew T.
AU - McNamara, Dan E.
AU - Guo, Hongyan
AU - Brown, Nathaniel W.
AU - Cao, Jennifer Yinuo
AU - Grace, Christy R.
AU - Gough, Peter J.
AU - Bertin, John
AU - Dixon, Scott J.
AU - Fiedler, Dorothea
AU - Mocarski, Edward S.
AU - Kaiser, William
AU - Moldoveanu, Tudor
AU - York, John D.
AU - Carette, Jan E.
PY - 2018/6/7
Y1 - 2018/6/7
N2 - Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death. Dovey et al. report an unexpected layer of regulation governing a form of cell death termed necroptosis. They find that the inositol phosphate code controls the executioner protein MLKL to induce cell lysis. This study deepens our understanding of cell death mechanisms important for infection, inflammation, and cancer.
AB - Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death. Dovey et al. report an unexpected layer of regulation governing a form of cell death termed necroptosis. They find that the inositol phosphate code controls the executioner protein MLKL to induce cell lysis. This study deepens our understanding of cell death mechanisms important for infection, inflammation, and cancer.
KW - cell death
KW - inositol phosphate
KW - IP kinase
KW - IPMK
KW - ITPK1
KW - MLKL
KW - necroptosis
KW - proinflammatory cytokine
KW - regulated necrosis
KW - RIPK3
UR - http://www.scopus.com/inward/record.url?scp=85047320671&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047320671&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2018.05.010
DO - 10.1016/j.molcel.2018.05.010
M3 - Article
C2 - 29883610
AN - SCOPUS:85047320671
VL - 70
SP - 936-948.e7
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -