Autophagy: From Membrane Movement to Nuclear Regulation.

Abstract

Autophagy, an evolutionarily conserved catabolic pathway, degrades long-lived proteins and organelles in response to internal and external stressors. This process is critical for maintaining cellular homeostasis and is essential to proper development and differentiation in higher eukaryotes. Autophagy is also a key player in the immune system, removing invading pathogens and aiding in the presentation of MHC antigens. The dysregulation of autophagy has been implicated in a variety of human diseases including neurodegeneration, cancer, and cardiovascular disorders. During autophagy, cytoplasmic materials are sequestered into double-membrane vesicles called autophagosomes. The autophagosome delivers its cargo to the lysosome (the vacuole in yeast) where it is degraded. Progress has been made in the identification of the proteins and mechanisms involved in this pathway, but much is still unknown, limiting our ability to target autophagy for therapeutic treatments. Two main unknowns are the source of the autophagosomal membrane and regulatory control. Here I present the work I have done to shed more light on these areas. Ypt1, an early secretory Rab protein, and its autophagy-specific guanine nucleotide exchange factor (GEF), TRAPPIII work together to transport membrane to the PAS. When either protein is dysfunctional, they fail to localize to the PAS and a key autophagosome assembly protein, Atg8, becomes mislocalized. When it comes to regulatory control of autophagy, there is an evolutionarily conserved histone switch. Acetylation of histone 4 lysine 16 (H4K16ac) must occur in order for autophagy to be cytoprotective. Additionally, H4K16ac is important in the promotion of ATG8 transcription and autophagy induction. Upon induction of autophagy there is an increase in the expression of the histone acetyltransferase Sas2, which is responsible for H4K16ac at the ATG8 promoter. Sas2 is then degraded, allowing for the loss of H4K16ac which prevents excessive autophagy and promotes cell survival. By furthering our understanding of both the autophagosomal membrane and the nuclear regulation of autophagy we can work to develop specific therapeutics to modulate autophagy in the treatment of disease.