The eIF2alpha kinases are a family of evolutionarily conserved serine/threonine kinases that regulate stress-induced translational arrest. Here, we demonstrate that the yeast eIF2alpha kinase, GCN2, ...the target phosphorylation site of Gcn2p, Ser-51 of eIF2alpha, and the eIF2alpha-regulated transcriptional transactivator, GCN4, are essential for another fundamental stress response, starvation-induced autophagy. The mammalian IFN-inducible eIF2alpha kinase, PKR, rescues starvation-induced autophagy in GCN2-disrupted yeast, and pkr null and Ser-51 nonphosphorylatable mutant eIF2alpha murine embryonic fibroblasts are defective in autophagy triggered by herpes simplex virus infection. Furthermore, PKR and eIF2alpha Ser-51-dependent autophagy is antagonized by the herpes simplex virus neurovirulence protein, ICP34.5. Thus, autophagy is a novel evolutionarily conserved function of the eIF2alpha kinase pathway that is targeted by viral virulence gene products.
KIL-d is a cytoplasmically inherited genetic trait which causes killer virus-infected cells of Saccharomyces cerevisiae to express the normal killer phenotypes in a/α cells, but to show variegated ...defective killer phenotypes in haploid cells. Mating of KIL-d haploids results in “healing” of their phenotypic defects, while meiosis of the resulting diploids results in “resetting” of the variegated, but mitotically stable, defects. This study shows that KIL-d does not reside on the dsRNA genome of killer virus. Thus, the KIL-d effect on viral gene expression is epigenetic in nature. Resetting requires nuclear events of meiosis, since KIL-d can be cytoplasmically transmitted during cytoduction without causing defects in killer virus expression. Subsequently, mating of these cytoductants followed by meiosis generates spore clones expressing variegated defective phenotypes. Cytoduction of wild-type cytoplasm into a phenotypically defective KIL-d haploid fails to heal, nor does simultaneous or sequential expression of both MAT alleles cause healing. Thus, healing is not triggered by the appearance of heterozygosity at the MAT locus, but rather requires the nuclear fusion events which occur during mating. Therefore, KIL-d appears to interact with the nucleus in order to exert its effects on gene expression by the killer virus RNA genome. Reversion studies show that the KIL-d element is spontaneously lost with a frequency of 10−4 to 10−5, and reappears with variegated phenotypic expression with a frequency of at least 10−3 This high rate of loss and higher rate of reappearance is unlike any known nucleic acid replicon but resembles the behavior of yeast prions. However, KIL-d is distinct from the known yeast prions in its relative guanidinium hydrochloride incurability and independence of HSPI04 protein for its maintenance. Despite its transmissibility by successive cytoplasmic transfers, multiple cytoplasmic nucleic acids have been proven not to carry the KIL-d trait. KIL-d epigenetically regulates the expression of the M dsRNA virus genome, but fails to alter the expression of M cDNA. This specificty remained even after a cycle of mating and meiosis. Due to its unique genetic properties and viral RNA specificity, KIL-d represents a new type of genetic element which interacts with a viral RNA genome.
The ubiquitin-proteasome and autophagy-lysosomal pathways are the two main routes of protein and organelle clearance in eukaryotic cells. The proteasome system is responsible for unfolded, ...short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.
Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau, and mutant and modified α-synuclein.
Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.
This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). The activation of p38 MAPK by GFAP accumulation is responsible for mTOR inactivation and the induction of autophagy. We also found that the accumulation of GFAP impairs proteasome activity.
In this commentary we discuss the potential compensatory relationship between an impaired proteasome and activated autophagy, and propose that the MLK-MAPK (mixed lineage kinase-mitogen-activated protein kinase) cascade is a regulator of this crosstalk. Addendum to: Tang G, Yue Z, Talloczy, Z, Hagemann T, Cho W, Sulzer D, Messing A, Goldman JE. Alexander disease-mutant GFAP accumulation stimulates autophagy through p38 MAPK and mTOR signaling pathways. Hum Mol Genetics 2008; In press.
![[KIL-d]: An epigenetic regu...](http://api.summon.serialssolutions.com/2.0.0/image/isbn/XR4PS5YY4K/9780599789234_0599789239/small "[KIL-d]: An epigenetic regulator of killer virus gene expression with prion -like genetics properties")