N52 monodeamidated Bcl‑xL shows impaired oncogenic properties in vivo and in vitro
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Florian Beaumatin1,2, Mohamad El Dhaybi1,2,4, Jean-Paul Lasserre1,2, Bénédicte Salin1,2, Mary Pat Moyer3, Mireille Verdier4, Stéphen Manon1,2, Muriel Priault1,2
1CNRS, Institut de Biochimie et de Génétique Cellulaires, UMR5095, 33077 Bordeaux, France
2Université Bordeaux Ségalen, Institut de Biochimie et de Génétique Cellulaires, UMR5095, 33077 Bordeaux, France
3INCELL Corporation, San Antonio, TX 78249, USA
4EA 3842, Homéostasie Cellulaire et Pathologies, Université de Limoges, 87025 Limoges cedex, France
Muriel Priault, e-mail: firstname.lastname@example.org
Keywords: Bcl-xL, autophagy, apoptosis, cancer, post-translational modification
Received: September 29, 2015 Accepted: January 31, 2016 Published: March 06, 2016
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.
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