Bag1-L is a phosphorylation-dependent coactivator of c-Jun during neuronal apoptosis.
In the nervous system, cell death by apoptosis plays a critical role during normal development and pathological neurodegeneration. Jun N-terminal kinases (JNKs) are essential regulators of neuronal apoptosis. The AP-1 transcription factor c-Jun is phosphorylated at multiple sites within its transactivation domain by the JNKs, and c-Jun phosphorylation is required for JNK-induced neurotoxicity. While the importance of c-Jun as a mediator of apoptotic JNK signaling in neurons is firmly established, the molecular mechanism underlying the requirement for c-Jun N-terminal phosphorylation is enigmatic. Here we identify the multifunctional protein Bag1-L as a coactivator of phosphorylated c-Jun. Bag1-L preferentially interacts with N-terminally phosphorylated c-Jun, and Bag1-L greatly augments transcriptional activation by phosphorylated c-Jun. Chromatin immunoprecipitation experiments revealed binding of Bag1-L to the promoters of proapoptotic AP-1 target genes, and overexpression of Bag1-L augmented cell death in primary neurons. Therefore, Bag1-L functions as a coactivator regulating neurotoxicity mediated by phosphorylated c-Jun.
Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, Lincoln's Inn Fields, London, United Kingdom.
Clive R
CR
Da Costa
Javier
J
Villadiego
Rocio
R
Sancho
Xavier
X
Fontana
Graham
G
Packham
Abdolrahman S
AS
Nateri
Axel
A
Behrens
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D004268:DNA-Binding Proteins; D020935:MAP Kinase Signaling System / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors