ABSTRACT
Viruses co-evolve with their hosts, and many viruses have developed mechanisms to suppress or modify the host cell apoptotic response for their own benefit. Recently, evidence has emerged for the opposite strategy. Some viruses have developed the ability to co-opt apoptotic caspase activity to facilitate their own proliferation. In these strategies, viral proteins are cleaved by host caspases to create cleavage products with novel activities which facilitate viral replication. This represents a novel and interesting class of viral-host interactions, and also represents a new group of non-apoptotic roles for caspases. Here we review the evidence for such strategies, and discuss their origins and their implications for our understanding of the relationship between viral pathogenesis and programmed cell death.
Subject(s)
Caspases/genetics , Host-Pathogen Interactions , Viral Proteins/genetics , Virus Diseases/enzymology , Viruses/genetics , Animals , Apoptosis , Caspases/metabolism , Gene Expression Regulation , Humans , Protein Biosynthesis , Proteolysis , Signal Transduction , Viral Proteins/metabolism , Virus Diseases/genetics , Virus Diseases/virology , Virus Replication , Viruses/growth & development , Viruses/metabolismABSTRACT
Differentiation of myoblasts into myotubes is essential for skeletal muscle development and regeneration. Caspase-3 and caspase-9 are required for efficient myoblast differentiation. The caspase-activated endonuclease activity, CAD, and the DNA-damage repair protein XRCC1 have also been shown to be required to complete differentiation. DNA-damage associated with differentiation is accompanied by phosphorylation of Histone 2AX, an event normally catalysed by kinases ATR, ATM or DNA-PK. However, the kinase responsible for phosphorylation during differentiation is not known. Here we show that inhibition of DNA-PK, but not of ATR or ATM, blocked histone phosphorylation during differentiation. We also show that DNA-PK inhibition and siRNA-mediated DNA-PK knockdown blocked cell fusion. These data implicate a new role for DNA-PK in myogenic differentiation.
Subject(s)
Caspase 3/metabolism , DNA-Activated Protein Kinase/physiology , Muscle Development , Animals , Caspase Inhibitors/pharmacology , Cell Fusion , Cell Line , Chromones/pharmacology , DNA Damage , DNA-Activated Protein Kinase/antagonists & inhibitors , Histones/metabolism , Mice , Morpholines/pharmacology , Muscle Development/drug effects , Muscle Development/genetics , Myoblasts/drug effects , Myoblasts/enzymology , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacologyABSTRACT
It has become increasingly clear that caspases, far from being merely cell death effectors, have a much wider range of functions within the cell. These functions are as diverse as signal transduction and cytoskeletal remodeling, and caspases are now known to have an essential role in cell proliferation, migration, and differentiation. There is also evidence that apoptotic cells themselves can direct the behavior of nearby cells through the caspase-dependent secretion of paracrine signaling factors. In some processes, including the differentiation of skeletal muscle myoblasts, both caspase activation in differentiating cells as well as signaling from apoptotic cells has been reported. Here, we review the non-apoptotic outcomes of caspase activity in a range of different model systems and attempt to integrate this knowledge.
