,11 p53 binding protein-1 (53BP1) participates in checkpoint signaling during the DNA damage response (DDR) and during mitosis. In this study we report that 53BP1 aggregates in nuclear foci within syncytia elicited by the human immunodeficiency virus (HIV)-1 envelope. 53BP1 aggregation occurs as a consequence of nuclear fusion (karyogamy (KG)). It colocalizes partially with the promyelomonocytic leukemia protein (PML), and the ataxia telangiectasia mutated kinase (ATM), the two components of the DDR that mediate apoptosis induced by the HIV-1 envelope. ATM-dependent phosphorylation of 53BP1 on serines 25 and 1778 (53BP1S25P and 53BP1S1778P) occurs at these DNA damage foci. 53BP1S25P was also detected in syncytia present in the lymph nodes or frontal brain sections from HIV-1-infected carriers, as well as in peripheral blood mononucleated cells from HIV-1-infected individuals, correlating with viral load. Knockdown of 53BP1 caused HIV-1 envelope-induced syncytia to enter abnormal mitoses, leading to their selective destruction through mitochondrion-dependent and caspase-dependent pathways. In conclusion, depletion of 53BP1 triggers the demise of HIV-1-elicited syncytia through mitotic catastrophe. The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by multiple mechanisms. 1 A soluble Env derivative, gp120, kills cells through signals that are transmitted by chemokine receptors such as CXCR4. 2-4 Cell surface-bound Env (composed by gp120 and gp41), which is present on the plasma membrane of HIV-1-infected cells, kills uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by several distinct mechanisms. First, transient interactions involving the exchange of lipids between the two interacting cells ('the kiss of death') without cell fusion may lead to the death of CD4-expressing target cells. Second, fusion of the interacting cells may initiate the formation of syncytia, which then succumb to apoptosis in a complex signaling pathway involving the activation of multiple kinases (ataxia teleangiectasia mutated (ATM), cyclin-dependent kinase-1 (Cdk1), checkpoint kinase-2 (Chk2), mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase (p38 MAPK) and inhibitor of NF-kB kinase, (IKK)), 5-9 as well as the activation of several transcription factors (NF-kB and p53), 2,10 finally resulting in the activation of the mitochondrial pathway of apoptosis. 11,12 These lethal signal transducers have been detected in the tissues of patients, within syncytia that are formed in the lymphatic tissues and the brain from HIV-1 carriers. At the apex of this apoptotic pathway, a DNA damage response (DDR) is triggered. After fusion of Env-exposing and uninfected cells, the nuclei contained in the common cytoplasm first remain separated and then fuse. The nonphysiological juxtaposition of non-synchronized genomes then triggers a DDR that involves the aggregation of the promyelocytic leukemia protein (PML) and the...
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