DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells.
Expression of adenovirus E1A deregulates cell proliferation to facilitate viral DNA replication, prompting the initiation of apoptosis signaled primarily through proapoptotic BAK in productively infected cells. We demonstrate here that in uninfected cells, BAK is complexed with the anti-apoptotic BCL-2 family member Myeloid Cell Leukemia 1 (MCL-1). E1A expression during infection resulted in the specific down-regulation of MCL-1 through destabilization of the protein and loss of the mRNA. Upon loss of the MCL-1-BAK complex, BAK complexed with either BAX in proapoptotic E1B mutant adenovirus-infected cells, or with the adenovirus BCL-2 homolog E1B 19K in cells infected with the wild-type virus in which apoptosis is inhibited. Loss of MCL-1 was required to initiate the apoptotic pathway in infected cells as restoration of MCL-1 expression rescued infected cells from E1A-induced apoptosis. Analogous to E1A expression, DNA damage down-regulates MCL-1, and adenovirus infection resulted in the accumulation of phosphorylated H2AX and ataxia-telangiectasia mutant protein (ATM), hallmarks of DNA double-strand breaks. Thus, MCL-1 may function by maintaining BAK in an inactive state, and the loss of MCL-1 upon activation of the DNA damage response, perhaps through replication stress induced in virus infected cells, may be required to initiate the apoptotic response.
Cuconati
Andrea
A
Howard Hughes Medical Institute, Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854, USA.
Mukherjee
Chandreyee
C
Perez
Denise
D
White
Eileen
E
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers; D004279:DNA, Viral / Q000096:biosynthesis; D015536:Down-Regulation; D019084:Fluorescent Antibody Technique, Indirect; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein
C494772:BAK1 protein, human; D017931:DNA Primers; D004279:DNA, Viral; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050998:bcl-2 Homologous Antagonist-Killer Protein