Autophagy: one more Nobel Prize for yeast.

The recent announcement of the 2016 Nobel Prize in Physiology or Medicine, awarded to Yoshinori Ohsumi for the discoveries of mechanisms governing autophagy, underscores the importance of intracellular degradation and recycling. At the same time, it further cements yeast, in which this field decisively developed, as a prolific model organism. Here we provide a quick historical overview that mirrors both the importance of autophagy as a conserved and essential process for cellular life and death as well as the crucial role of yeast in its mechanistic characterization.

A histone point mutation that switches on autophagy.

The multifaceted process of aging inevitably leads to disturbances in cellular metabolism and protein homeostasis. To meet this challenge, cells make use of autophagy, which is probably one of the most important pathways preserving cellular protection under stressful conditions. Thus, efficient autophagic flux is required for healthy aging in many if not all eukaryotic organisms.

Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan.

Healthy aging depends on removal of damaged cellular material that is in part mediated by autophagy. The nutritional status of cells affects both aging and autophagy through as-yet-elusive metabolic circuitries. Here, we show that nucleocytosolic acetyl-coenzyme A (AcCoA) production is a metabolic repressor of autophagy during aging in yeast.

Regulation of autophagy by cytosolic acetyl-coenzyme A.

Acetyl-coenzyme A (AcCoA) is a major integrator of the nutritional status at the crossroads of fat, sugar, and protein catabolism. Here we show that nutrient starvation causes rapid depletion of AcCoA. AcCoA depletion entailed the commensurate reduction in the overall acetylation of cytoplasmic proteins, as well as the induction of autophagy, a homeostatic process of self-digestion.

Nucleotide-hydrolyzing antibodies from the sera of autoimmune-prone MRL-lpr/lpr mice.

Abzymes (Abzs) with different enzymic activities have been detected in the sera of patients with various autoimmune (AI) diseases and in AI mice. In this work, electrophoretically homogeneous IgGs were isolated from the sera of MRL-lpr/lpr mice spontaneously developing lupus-like AI pathology. It was shown for the first time that polyclonal IgGs (pIgGs) and their isolated heavy and light chains hydrolyze different nucleoside-5'-triphosphate (NTPs), nucleoside-5'-diphosphate (NDPs), adenosine monophosphate and deoxiadenosine-5'-monophosphate (dAMP), whereas antibodies from the sera of control healthy mice were catalytically inactive.

Substrate binding in the FAD-dependent hydroxynitrile lyase from almond provides insight into the mechanism of cyanohydrin formation and explains the absence of dehydrogenation activity.

In a large number of plant species hydroxynitrile lyases catalyze the decomposition of cyanohydrins in order to generate hydrogen cyanide upon tissue damage. Hydrogen cyanide serves as a deterrent against herbivores and fungi. In vitro hydroxynitrile lyases are proficient biocatalysts for the stereospecific synthesis of cyanohydrins.

Formation of different abzymes in autoimmune-prone MRL-lpr/lpr mice is associated with changes in colony formation of haematopoietic progenitors.

It was shown that IgGs from the sera of 2-7-month-old control non-autoimmune (CBA x C57BL)F1 and BALB/c mice and 2-3-month-old autoimmune prone MRL-lpr/lpr mice (conditionally healthy mice) are catalytically inactive. During spontaneous development of deep systemic lupus erythematosus (SLE)-like pathology a specific reorganization of immune system of these mice leads to conditions associated with a production of IgGs hydrolyzing DNA, ATP and polysaccharides with low catalytic activities (conditionally pre-diseased mice).A significant increase in DNase, ATPase and amylase IgG relative activities associated with a transition from pre-diseased to deep diseased mice is correlated with additional changes in differentiation and proliferation of mice bone marrow haematopoietic stem cells (HSCs) and lymphocyte proliferation in different organs.

Antibodies with amylase activity from the sera of autoimmune-prone MRL/MpJ-lpr mice.

Animals spontaneously developing lupus-like autoimmune pathology (SLE) are very promising models to study the mechanisms of natural abzymes (Abzs) generation and their role in etiology and pathogenesis of autoimmune diseases, but Abzs from the sera of animals remain virtually unstudied. In this work, electrophoretically homogeneous IgGs were isolated from the sera of MRL/MpJ-lpr mice. It was shown for the first time that amylase activity is an intrinsic property of antibodies (Abs) and their isolated heavy and light chains.

DNA-hydrolyzing antibodies from sera of autoimmune-prone MRL/MpJ-lpr mice.

Catalytically active antibodies (abzymes) hydrolyzing proteins, polysaccharides, ATP, DNA, and RNA have been detected in the sera of patients with various autoimmune and some viral diseases, but abzymes from the sera of animals are practically unstudied. The development of lupus-like autoimmune disease of MRL/MpJ-lpr mice is an experimental model for study of autoimmune pathologies and immunopathogenesis. In this work, homogeneous IgG preparations were isolated from the sera of MRL/MpJ-lpr mice.