Article

Viral modulators of cell death provide new links to old pathways.

Department of Molecular Microbiology, Johns Hopkins Schools of Medicine and Public Health, 615 North Wolfe St, Baltimore, Maryland 21205, USA.
Current Opinion in Cell Biology (Impact Factor: 11.41). 01/2004; 15(6):700-5. DOI: 10.1016/j.ceb.2003.10.007
Source: PubMed

ABSTRACT By observing how viruses facilitate their parasitic relationships with host cells, we gain insights into key regulatory pathways of the cell. Not only are mitochondria key players in the regulation of programmed cell death, but many viral regulators of cell death also alter mitochondrial functions either directly or indirectly. Although cytomegalovirus vMIA and Epstein-Barr virus BHRF1 seem to have opposite effects on mitochondrial morphology, they both inhibit cell death. Drosophila Reaper, a regulator of developmental cell death, acts on IAP (inhibitor of apoptosis) proteins to activate caspases, but can regulate mitochondrial permeability in vitro. Despite its pivotal role in Drosophila, homologues of Reaper in other species were not previously known. Recently, amino acid sequence similarity was recognized between Drosophila Reaper and a protein known to be important for the replication and virulence of mosquito-borne bunyaviruses that cause human encephalitis. Thus, viral mechanisms for regulating apoptosis are diverse and not fully elucidated but promise to provide new insights.

0 Bookmarks
 · 
77 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
    Cold Spring Harbor perspectives in biology 01/2013; 5(2). · 9.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Arthropoda is the largest of all animal phyla and includes about 90% of extant species. Our knowledge about regulation of apoptosis in this phylum is largely based on findings for the fruit fly Drosophila melanogaster. Recent work with crustaceans shows that apoptotic proteins, and presumably mechanisms of cell death regulation, are more diverse in arthropods than appreciated based solely on the excellent work with fruit flies. Crustacean homologs exist for many major proteins in the apoptotic networks of mammals and D. melanogaster, but integration of these proteins into the physiology and pathophysiology of crustaceans is far from complete. Whether apoptosis in crustaceans is mainly transcriptionally regulated as in D. melanogaster (e.g., RHG 'killer' proteins), or rather is controlled by pro- and anti-apoptotic Bcl-2 family proteins as in vertebrates needs to be clarified. Some phenomena like the calcium-induced opening of the mitochondrial permeability transition pore (MPTP) are apparently lacking in crustaceans and may represent a vertebrate invention. We speculate that differences in regulation of the intrinsic pathway of crustacean apoptosis might represent a prerequisite for some species to survive harsh environmental insults. Pro-apoptotic stimuli described for crustaceans include UV radiation, environmental toxins, and a diatom-produced chemical that promotes apoptosis in offspring of a copepod. Mechanisms that serve to depress apoptosis include the inhibition of caspase activity by high potassium in energetically healthy cells, alterations in nucleotide abundance during energy-limited states like diapause and anoxia, resistance to opening of the calcium-induced MPTP, and viral accommodation during persistent viral infection. Characterization of the players, pathways, and their significance in the core machinery of crustacean apoptosis is revealing new insights for the field of cell death.
    Apoptosis 03/2010; 15(3):293-312. · 4.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to cancer. Found at the outer mitochondrial membrane, VDAC1 assumes a crucial position in the cell, controlling the metabolic cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. As a metabolite transporter, VDAC1 contributes to the metabolic phenotype of cancer cells. This is reflected by VDAC1 over-expression in many cancer types, and by inhibition of tumor development upon silencing VDAC1 expression. Along with regulating cellular energy production and metabolism, VDAC1 is also a key protein in mitochondria-mediated apoptosis, participating in the release of apoptotic proteins and interacting with anti-apoptotic proteins. The involvement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space is discussed, as is VDAC1 oligomerization as an important step in apoptosis induction. VDAC also serves as an anchor point for mitochondria-interacting proteins, some of which are also highly expressed in many cancers, such as hexokinase (HK), Bcl2, and Bcl-xL. By binding to VDAC, HK provides both metabolic benefit and apoptosis-suppressive capacity that offers the cell a proliferative advantage and increases its resistance to chemotherapy. VDAC1-based peptides that bind specifically to HK, Bcl2, or Bcl-xL abolished the cell's abilities to bypass the apoptotic pathway. Moreover, these peptides promote cell death in a panel of genetically characterized cell lines derived from different human cancers. These and other functions point to VDAC1 as a rational target for the development of a new generation of therapeutics.
    Frontiers in Oncology 01/2012; 2:164.

Full-text (2 Sources)

View
18 Downloads
Available from
May 29, 2014