Apoptosis in the development of the immune system

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117

The galectin family of lectins regulates multiple biologic functions, such as development, inflammation, immunity, and cancer. One common function of several galectins is the ability to trigger T cell death. However, differences among the death pathways triggered by various galectins with regard to glycoprotein receptors, intracellular death pathways, and target cell specificity are not well understood. Specifically, galectin-9 and galectin-1 both kill thymocytes, peripheral T cells, and T cell lines; however, we have found that galectin-9 and galectin-1 require different glycan ligands and glycoprotein receptors to trigger T cell death. The two galectins also utilize different intracellular death pathways, as galectin-9, but not galectin-1, T cell death was blocked by intracellular Bcl-2, whereas galectin-1, but not galectin-9, T cell death was blocked by intracellular galectin-3. Target cell susceptibility also differed between the two galectins, as galectin-9 and galectin-1 killed different subsets of murine thymocytes. To define structural features responsible for distinct activities of the tandem repeat galectin-9 and dimeric galectin-1, we created a series of bivalent constructs with galectin-9 and galectin-1 carbohydrate recognition domains connected by different peptide linkers. We found that the N-terminal carbohydrate recognition domain and linker peptide contributed to the potency of these constructs. However, we found that the C-terminal carbohydrate recognition domain was the primary determinant of receptor recognition, death pathway signaling, and target cell susceptibility. Thus, carbohydrate recognition domain specificity, presentation, and valency make distinct contributions to the specific effects of different galectins in initiating T cell death.Cell death is an essential factor in T cell development, which regulates selection of functional T cells during development in the thymus, as well as elimination of activated T cells after microbial infection or other exposure to antigen (1, 2). A number of distinct T cell death pathways have been described, including those triggered by members of the galectin family of vertebrate lectins (3-5). Galectin-1 was the first family member described to induce death of developing thymocytes and activated peripheral T cells, and the galectin-1 T cell death pathway is the best characterized to date. Specific glycoprotein receptors involved in galectin-1 death and specific types of O-and N-glycan ligands required for galectin-1 death have been identified, and galectin-1 has been shown to trigger a novel intracellular death pathway (6 -14). Other galectins have also been reported to trigger death of T cell lines and various T cell subsets, including galectin-2, galectin-3, galectin-8, and galectin-9 (15-19). Relatively little is known about the glycoprotein receptors, glycan ligands, and intracellular death pathways used by these galectins. However, our laboratory has found that galectin-1 and galectin-3 kill different subsets of thymocytes, and use distinct sets...

mentioning

confidence: 99%

Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

Earl

Jacobs

et al. 2008

131

117

“…The BH3-only-containing proapoptotic members, which include Bim, Puma, Bid, and Noxa, promote apoptosis by directly binding and inducing the oligomerizaton of Bak and/or Bax or by neutralizing the antiapoptotic members. The antiapoptotic family members directly bind and antagonize Bak and Bax or sequester the BH3-only family members to prevent interactions with the effectors (17)(18)(19). In AML cells, various reagents have been described to induce apoptosis via altering levels of different Bcl-2 family members, suggesting that AML cells are sensitive to regulation of Bcl-2 family proteins (20 -23).…”

mentioning

confidence: 99%

CXCR4 Chemokine Receptor Signaling Induces Apoptosis in Acute Myeloid Leukemia Cells via Regulation of the Bcl-2 Family Members Bcl-XL, Noxa, and Bak

Kremer¹,

Peterson²,

Schneider³

et al. 2013

Background:The chemokine receptor CXCR4 plays a role in AML. Results: SDF-1, the ligand of CXCR4, induces apoptosis in AML cell lines and patient samples via modulation of Bcl-2 family members. Conclusion: SDF-1 induces apoptosis of AML cells via up-regulation of Bak and Noxa and down-regulation of Bcl-X L . Significance: SDF-1/CXCR4 signaling could induce AML cell apoptosis if bone marrow survival cues can be disrupted.

“…The cell corpses are then cleanly removed by phagocytes obviating inflammatory and autoimmune responses (4). Apoptosis is vital for development and homeostasis of metazoans (5)(6)(7), and malfunction of the human apoptosis machinery is implicated in autoimmune diseases, neurodegenerative disorders, and cancer (8 -11).…”

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confidence: 99%

A New Model for the Transition of APAF-1 from Inactive Monomer to Caspase-activating Apoptosome

Reubold

Wohlgemuth

Eschenburg

2009

The cytosolic adaptor protein Apaf-1 is a key player in the intrinsic pathway of apoptosis. Binding of mitochondrially released cytochrome c and of dATP or ATP to Apaf-1 induces the formation of the heptameric apoptosome complex, which in turn activates procaspase-9. We have re-investigated the chain of events leading from monomeric autoinhibited Apaf-1 to the functional apoptosome in vitro. We demonstrate that Apaf-1 does not require energy from nucleotide hydrolysis to eventually form the apoptosome. Despite a low intrinsic hydrolytic activity of the autoinhibited Apaf-1 monomer, nucleotide hydrolysis does not occur at any stage of the process. Rather, mere binding of ATP in concert with the binding of cytochrome c primes Apaf-1 for assembly. Contradicting the current view, there is no strict requirement for an adenine base in the nucleotide. On the basis of our results, we present a new model for the mechanism of apoptosome assembly.Cells of most multicellular organisms can terminate themselves conducting the evolutionary conserved program of apoptosis. As the well regulated response to a death signal from outside or inside the cell, a cascade of cysteine proteases, socalled caspases, is activated that eventually leads to the orderly disintegration of cell organelles and chromatin (1-3). In contrast to necrotic cell death, which is accompanied by inflammation and damage of the surrounding tissue, apoptotic cells keep their degraded constituents contained in intact membrane. The cell corpses are then cleanly removed by phagocytes obviating inflammatory and autoimmune responses (4). Apoptosis is vital for development and homeostasis of metazoans (5-7), and malfunction of the human apoptosis machinery is implicated in autoimmune diseases, neurodegenerative disorders, and cancer (8 -11).The intrinsic pathway of apoptosis responds to cytotoxic stress, genomic damage, and developmental cues (12, 13). The pivotal point of this pathway is the release of cytochrome c from the mitochondria through permeabilization of the outer membrane (14, 15). In human cells, transduction of this decisive death signal is achieved via the 142-kDa cytosolic protein Apaf-1, the mammalian ortholog of Caenorhabditis elegans CED-4 (16). Apaf-1 contains an N-terminal caspase recruitment domain (CARD), 2 a central nucleotide binding and oligomerization domain (NOD), and a C-terminal regulatory domain of 13 WD40 repeats. It is thought that the WD40 repeat domain blocks the CARD and NOD until cytochrome c is released into the cytosol (17-20). Binding of cytochrome c to the WD40 repeat domain in the presence of ATP or dATP appears to induce a large conformational change in Apaf-1 that eventually bares the NOD and the effector-binding CARD. Mediated by the NOD, Apaf-1 oligomerizes into a wheel-like heteroheptameric protein complex (21) termed apoptosome. The apoptosome recruits the initiator caspase-9 via homophilic CARD-CARD interaction and the holoenzyme then activates downstream executioner caspases (22-24).So far, there is no consistent view...