From zero to sixty: cell death signaling in the city that never sleeps.

Abstract

In a blistery winter of New York City, over 120 researchers congregated at the Icahn School of Medicine at Mount Sinai for the first Cell Death Signaling conference (Figure 1). Manhattan’s Upper East Side was the setting for 2 days of presentations to discuss a topic relevant to all life: cell death. The mechanisms by which cells generate and respond to death signals remain of tremendous interest, and this is particularly true with regard to diseases in which cell death regulation is disrupted. As such, this conference served to bring together cutting edge research from the fields of cell death, metabolism, immunology, autophagy and cancer. In addition, the conference coincided with the sixtieth birthday of Douglas R Green PhD, Oncogene Editor-in-Chief. In celebration of his many contributions and accomplishments, speakers highlighted the influence Doug has on the cell death community, both scientifically and personally. As a result, state of the art cell death research was juxtaposed with a celebration of scientific accomplishments, and here we provide a summary of the 25 presentations and describe general themes emerging in the field. Figure 1 Cell Death Signaling 2015 guests and speakers. Speakers and invited guests of the meeting congregated at the Temple of Dendur in the Metropolitan Museum of Art in New York City‘s Upper East Side. The guest of honor, Douglas R Green PhD, was greeted ... IF IT AIN’T BROKE, DON’T KILL IT: MECHANISMS OF CELL DEATH AND MAINTENANCE A meeting about cell death signaling would be incomplete without appropriate coverage of the different forms of caspase-mediated cell death. Guy Salvesen (Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA) discussed the discovery and history of caspases, the evolutionarily conserved proteases of cell death, as well as the pathways for which they are required. Apoptosis, the cell death pathway defined by caspase activation, occurs when effector caspases-3/-6/-7 cleave a variety of cellular substrates resulting in the phenotypic hallmarks of apoptosis. The effector caspases can be activated downstream of two distinct pathways: extracellular signals can interact with cell-surface receptors (such as those in the TNF receptor family) and lead to accumulation and activation of initiator caspase-8. Alternatively, intrinsic cell stress (such as damage or nutrient deprivation) signals through the BCL-2 family of proteins, initiating permeabilization of the outer mitochondrial membrane (OMM), release of proteins from the inner-membrane space (cytochrome c), formation of the apoptosome, and finally, activation of initiator caspase-9 and downstream effector caspases. Other forms of cell death include necroptosis, which occurs in the absence or restriction of caspase action, and pyroptosis, a recently defined form of cell death that utilizes alternative caspases-1/-11. Seamus Martin (Trinity College Dublin, Dublin, Ireland) discussed the consequences of cells dying through these mechanisms and the resulting uncontrolled release of internal components into the surrounding environment. Cells succumbing to unregulated methods of death create an inflammatory response when released chemokines and cytokines signal resident neutrophils and macrophages. In addition, released cellular components (ATP, DNA fragments) function as damage associated molecular patterns (DAMPs) and initiate pro-inflammatory signaling cascades through pattern recognition receptors (PRRs). However, Martin remarked that the list of cellular proteins or molecules that may act as DAMPs remains largely unexplored. In contrast, regulated secretion of cytokines occurs during pyroptosis when pathogen-associated molecular patterns bind cytosolic PRRs and activate the inflammasome. Thirumala-Devi Kanneganti (St Jude Children’s Research Hospital, Memphis, TN, USA) introduced work demonstrating that in response to Aspergillus infection, AIM2 and NLRP3 orchestrate the formation of the inflammasome proteins ASC and caspase-1, resulting in the proteolytic cleavage and activation of IL-1β and IL-18. These cytokines create an inflammatory response through recruitment of leukocytes and lymphocytes. Interestingly, work by William Evans (St Jude Children’s Research Hospital) demonstrated that patients with prednisolone-resistant acute lymphoblastic leukemia (ALL) had increased expression of NLRP3 and caspase-1. This over-expression results in inappropriate caspase activation, increased secretion of IL-1β and IL-18, and cleavage of the glucocorticoid receptor, making patients insensitive to the corticosteroid drug. Patient response to prednisolone remains prognostic of ALL outcomes and the observed increased expression of inflammasome NLRP3 may serve as a potential new therapeutic target.