MLKL: Mixed Lineage Kinase Domain Like Pseudokinase
Key Executor of Necroptosis and Inflammatory Signaling
Gene Information Card
| Symbol | MLKL |
|---|---|
| Full Name | Mixed Lineage Kinase Domain Like Pseudokinase |
| Gene Type | Protein coding |
| Chromosomal Location | 16q23.1 |
| NCBI Gene ID | 197259 ncbi.nlm.nih.gov/gene/197259 |
| Ensembl ID | ENSG00000168404 |
| UniProt ID | Q8NB16 |
| OMIM ID | 615153 |
| HGNC ID | 26617 |
| Aliases | hMLKL, FLJ34389, MGC18216 |
Description
MLKL (Mixed Lineage Kinase Domain Like Pseudokinase) is a pseudokinase that serves as the core executioner of necroptosis, a form of programmed necrotic cell death. Upon phosphorylation by RIPK3, MLKL oligomerizes and translocates to the plasma membrane, disrupting membrane integrity and leading to cell lysis. MLKL is also implicated in inflammatory signaling, immune responses, and various pathological conditions including ischemic injury, neurodegenerative diseases, and cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Inflammatory bowel disease (IBD) | MLKL-mediated necroptosis in intestinal epithelial cells drives inflammation and tissue damage | GWAS and functional studies (PMID: 31073040) |
| Ischemia-reperfusion injury | MLKL activation in cardiomyocytes and renal tubular cells promotes necrotic cell death during reperfusion | Animal models and in vitro studies (PMID: 27559042) |
| Non-alcoholic steatohepatitis (NASH) | Hepatocyte necroptosis via MLKL contributes to liver inflammation and fibrosis | Mouse models and human biopsies (PMID: 27559042) |
| Cancer (various types) | Dysregulated MLKL expression influences tumor cell survival and immune evasion; context-dependent pro- or anti-tumor roles | Expression and functional studies (PMID: 31073040) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | 5.8 | Low |
| Lymph node | 4.2 | Low |
| Spleen | 3.9 | Low |
| Lung | 2.1 | Low |
| Small intestine | 1.8 | Low |
| Colon | 1.5 | Low |
| Heart | 0.8 | Not detected |
| Brain | 0.5 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| THP-1 (monocyte) | 3.2 | Differentiated macrophages show higher expression |
| Jurkat (T cell) | 2.5 | Activation increases MLKL levels |
| HeLa (cervical) | 1.9 | Basal expression |
| HEK293 (embryonic kidney) | 1.5 | Common model for necroptosis studies |
| HepG2 (liver) | 1.2 | Low baseline, inducible by stress |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1?) | Missense | <0.01% | Likely loss of start codon; functional impact unknown |
| c.104C>T (p.Pro35Leu) | Missense | <0.01% | Rare variant; no known disease association |
| c.1135G>A (p.Glu379Lys) | Missense | <0.01% | Located in pseudokinase domain; effect unclear |
Mutation functional classification
Loss of Function (LOF)
Mutations that prevent MLKL oligomerization or membrane translocation (e.g., disruption of the four-helix bundle) abolish necroptosis execution.
Gain of Function (GOF)
Constitutive active mutants (e.g., phosphomimetic S345D/S347D in mouse) trigger necroptosis independently of RIPK3.
Dominant Negative (DN)
Truncated or oligomerization-deficient MLKL variants can inhibit necroptosis by competing with wild-type MLKL for RIPK3 binding.
View complete mutation data：
Gene Ontology (GO)
| • GO:0005515 (protein binding) | • GO:0005524 (ATP binding) |
| • GO:0004672 (protein kinase activity) | • GO:0004674 (protein serine/threonine kinase activity) |
| • GO:0006915 (apoptotic process) | • GO:0070266 (necroptotic process) |
| • GO:0005886 (plasma membrane) | • GO:0005737 (cytoplasm) |
Pathways
• Necroptosis (KEGG: hsa04217)
• RIPK1/RIPK3/MLKL signaling (Reactome: R-HSA-5213460)
• Programmed cell death (WikiPathways: WP3913)
Protein Summary
MLKL is a 471-amino acid pseudokinase with an N-terminal four-helix bundle (4HB) domain responsible for membrane disruption, a central brace region, and a C-terminal pseudokinase domain that binds RIPK3. In its inactive state, MLKL exists as a monomer in the cytosol. Upon necroptotic signaling, RIPK3 phosphorylates MLKL at Thr357 and Ser358 (human), inducing a conformational change that exposes the 4HB domain, promotes oligomerization, and triggers translocation to the plasma membrane. There, MLKL inserts into the lipid bilayer, causing ion influx, cell swelling, and membrane rupture. MLKL also participates in inflammatory signaling by promoting the release of damage-associated molecular patterns (DAMPs).
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MLKL Knockout HEK293 Cell Line | EDJ-KQ1471 | Human | 197259 | Details Get a Quote |
| MLKL Knockout A-549 Cell Line | EDJ-KQ21043 | Human | 197259 | Details Get a Quote |
| MLKL Knockout HCT 116 Cell Line | EDJ-KQ21044 | Human | 197259 | Details Get a Quote |
| MLKL Knockout HeLa Cell Line | EDJ-KQ21045 | Human | 197259 | Details Get a Quote |
| Mlkl Knockout IBMDM Cell Line | EDC90296 | Mouse | 74568 | Details Get a Quote |
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