Abstract
Granzyme A (GzmA) induces a caspase-independent cell death pathway characterized by single-stranded DNA nicks and other features of apoptosis. A GzmA-activated DNase (GAAD) is in an ER associated complex containing pp32 and the GzmA substrates SET, HMG-2, and Ape1. We show that GAAD is NM23-H1, a nucleoside diphosphate kinase implicated in suppression of tumor metastasis, and its specific inhibitor (IGAAD) is SET. NM23-H1 binds to SET and is released from inhibition by GzmA cleavage of SET. After GzmA loading or CTL attack, SET and NM23-H1 translocate to the nucleus and SET is degraded, allowing NM23-H1 to nick chromosomal DNA. GzmA-treated cells with silenced NM23-H1 expression are resistant to GzmA-mediated DNA damage and cytolysis, while cells overexpressing NM23-H1 are more sensitive.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Active Transport, Cell Nucleus / genetics*
-
Apoptosis / genetics*
-
Carbon-Oxygen Lyases / genetics
-
Carbon-Oxygen Lyases / metabolism
-
Chromosomal Proteins, Non-Histone / genetics
-
Chromosomal Proteins, Non-Histone / metabolism*
-
DNA Fragmentation / genetics
-
DNA, Single-Stranded / genetics
-
DNA, Single-Stranded / metabolism
-
DNA-(Apurinic or Apyrimidinic Site) Lyase
-
DNA-Binding Proteins
-
Deoxyribonucleases / genetics
-
Deoxyribonucleases / metabolism
-
Gene Expression Regulation / genetics
-
Gene Silencing / physiology
-
Genes, Tumor Suppressor / physiology*
-
Granzymes
-
HMGB2 Protein / genetics
-
HMGB2 Protein / metabolism
-
HeLa Cells
-
Histone Chaperones
-
Humans
-
Immunity, Cellular / genetics*
-
Jurkat Cells
-
K562 Cells
-
Models, Biological
-
Monomeric GTP-Binding Proteins / genetics
-
Monomeric GTP-Binding Proteins / metabolism*
-
NM23 Nucleoside Diphosphate Kinases
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Nucleoside-Diphosphate Kinase*
-
Nucleosomes / metabolism
-
Phosphoproteins / genetics
-
Phosphoproteins / metabolism
-
Serine Endopeptidases / genetics
-
Serine Endopeptidases / metabolism*
-
T-Lymphocytes, Cytotoxic / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
Substances
-
Chromosomal Proteins, Non-Histone
-
DNA, Single-Stranded
-
DNA-Binding Proteins
-
HMGB2 Protein
-
Histone Chaperones
-
NM23 Nucleoside Diphosphate Kinases
-
Nuclear Proteins
-
Nucleosomes
-
Phosphoproteins
-
SET protein, human
-
Transcription Factors
-
NME1 protein, human
-
Nucleoside-Diphosphate Kinase
-
Deoxyribonucleases
-
Granzymes
-
Serine Endopeptidases
-
GZMA protein, human
-
Monomeric GTP-Binding Proteins
-
Carbon-Oxygen Lyases
-
APEX1 protein, human
-
DNA-(Apurinic or Apyrimidinic Site) Lyase