Abstract
Bcl-xL is a member of the Bcl-2 family, playing a critical role in the survival of tumor cells. Here, we show that Bcl-xL oncogenic function can be uncoupled from its anti-apoptotic activity when it is regulated by the post-translational deamidation of its Asn52.Bcl-xL activity can be regulated by post-translational modifications: deamidation of Asn52 and 66 into Asp residues was reported to occur exclusively in response to DNA damage, and to cripple its anti-apoptotic activity. Our work reports for the first time the spontaneous occurrence of monodeamidated Asp52Bcl-xL in control conditions, in vivo and in vitro. In the normal and cancer cell lines tested, no less than 30% and up to 56% of Bcl-xL was singly deamidated on Asn52. Functional analyses revealed that singly deamidated Bcl-xL retains anti-apoptotic functions, and exhibits enhanced autophagic activity while harboring impaired clonogenic and tumorigenic properties compared to native Bcl-xL. Additionally, Asp52Bcl-xL remains phosphorylatable, and thus is still an eligible target of anti-neoplasic agents. Altogether our results complement the existing data on Bcl-xL deamidation: they challenge the common acceptance that Asn52 and Asn66 are equally eligible for deamidation, and provide a valuable improvement of our knowledge on the regulation of Bcl-xLoncogenic functions by deamidation.
Highlights
Bcl‐xL is an oncogene whose over-expression is largely documented in cancers like colorectal adenocarcinoma [1], breast [2] and prostate cancer [3] and multiple myeloma [4]
Monodeamidated Asp52Bcl‐xL is readily detected in control-grown HCT116 colorectal cancer cells
A pioneering work by the Weintraub lab [21] combining SDS-polyacrylamide gel electrophoresis (PAGE) of Bcl‐xL deamidation mutants and tandem mass spectrometry, established that deamidation can be appraised by differences in the SDSPAGE migration profiles
Summary
Bcl‐xL is an oncogene whose over-expression is largely documented in cancers like colorectal adenocarcinoma [1], breast [2] and prostate cancer [3] and multiple myeloma [4]. A comparison of the two proteins carried out in a single cellular context further highlighted (i) that Bcl‐2 and Bcl‐xL exhibit functional differences in their inhibition of apoptosis depending on the death inducer and the pertaining signaling pathway, and (ii) that Bcl‐xL is more potent than Bcl‐2 to warrant cell survival [8] Another noticeable difference is the unique susceptibility of Bcl‐xL to undergo a post-translational modification (PTM) called deamidation in cells exposed www.impactjournals.com/oncotarget to DNA damaging agents, [9, 10]. Deamidation affects a great number of proteins (human growth hormone [12], calmodulin [13], tissue plasminogen activator [14], tubulin [15], synapsin [16], Alzheimer’s β-amyloid [17], histone H2B [18], protein kinase A [19], cytochrome c... [11]), and has wide biological repercussions because it can lead to structural changes and/or modify their life-span
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