Hsp90 and p23 Molecular Chaperones Control Chromatin Architecture by Maintaining the Functional Pool of the RSC Chromatin Remodeler.

Molecular chaperones govern protein homeostasis, being allied to the beginning (folding) and ending (degradation) of the protein life cycle. Yet, the Hsp90 system primarily associates with native factors, including fully assembled complexes. The significance of these connections is poorly understood. To delineate why Hsp90 and its cochaperone p23 interact with a mature structure, we focused on the RSC chromatin remodeler. Both Hsp90 and p23 triggered the release of RSC from DNA or a nucleosome. Although Hsp90 only freed bound RSC, p23 enhanced nucleosome remodeling prior to discharging the complex. In vivo, RSC mobility and remodeling function were chaperone dependent. Our results suggest Hsp90 and p23 contribute to proteostasis by chaperoning mature factors through energetically unfavorable events, thereby maintaining the cellular pool of active native proteins. In the case of RSC, p23 and Hsp90 promote a dynamic action, allowing a limited number of remodelers to effectively maintain chromatin in a pliable state.

The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy.

Autophagy is an evolutionarily conserved catabolic process involved in several physiological and pathological processes. Although primarily cytoprotective, autophagy can also contribute to cell death; it is thus important to understand what distinguishes the life or death decision in autophagic cells. Here we report that induction of autophagy is coupled to reduction of histone H4 lysine 16 acetylation (H4K16ac) through downregulation of the histone acetyltransferase hMOF (also called KAT8 or MYST1), and demonstrate that this histone modification regulates the outcome of autophagy. At a genome-wide level, we find that H4K16 deacetylation is associated predominantly with the downregulation of autophagy-related genes. Antagonizing H4K16ac downregulation upon autophagy induction results in the promotion of cell death. Our findings establish that alteration in a specific histone post-translational modification during autophagy affects the transcriptional regulation of autophagy-related genes and initiates a regulatory feedback loop, which serves as a key determinant of survival versus death responses upon autophagy induction.

The Ume6-Sin3-Rpd3 complex regulates ATG8 transcription to control autophagosome size.

The vast majority of studies addressing the induction of autophagy have focused upon cytoplasmic aspects of its regulation. Recently, we have started to expand our knowledge regarding the nuclear events of autophagic induction. Many autophagy-related genes are transcriptionally upregulated upon induction of autophagy, but only in a limited number of cases do we know the pathways leading to this upregulation. Few transcription factors have been implicated in controlling autophagy genes in yeast. However, many of the ATG genes show some level of transcriptional induction upon starvation. Now, we show that transcription of ATG8 is repressed under growing conditions by the Ume6-Sin3-Rpd3 complex.

Ume6 transcription factor is part of a signaling cascade that regulates autophagy.

Autophagy has been implicated in a number of physiological processes important for human heath and disease. Autophagy involves the formation of a double-membrane cytosolic vesicle, an autophagosome. Central to the formation of the autophagosome is the ubiquitin-like protein autophagy-related (Atg)8 (microtubule-associated protein 1 light chain 3/LC3 in mammalian cells). Following autophagy induction, Atg8 shows the greatest change in expression of any of the proteins required for autophagy. The magnitude of autophagy is, in part, controlled by the amount of Atg8; thus, controlling Atg8 protein levels is one potential mechanism for modulating autophagy activity. We have identified a negative regulator of ATG8 transcription, Ume6, which acts along with a histone deacetylase complex including Sin3 and Rpd3 to regulate Atg8 levels; deletion of any of these components leads to an increase in Atg8 and a concomitant increase in autophagic activity. A similar regulatory mechanism is present in mammalian cells, indicating that this process is highly conserved.

The role of autophagy in Parkinson's disease.

Great progress has been made toward understanding the pathogenesis of Parkinson's disease (PD) during the past two decades, mainly as a consequence of the discovery of specific gene mutations contributing to the onset of PD. Recently, dysregulation of the autophagy pathway has been observed in the brains of PD patients and in animal models of PD, indicating the emerging role of autophagy in this disease. Indeed, autophagy is increasingly implicated in a number of pathophysiologies, including various neurodegenerative diseases. This article will lead you through the connection between autophagy and PD by introducing the concept and physiological function of autophagy, and the proteins related to autosomal dominant and autosomal recessive PD, particularly α-synuclein and PINK1-PARKIN, as they pertain to autophagy.

The Cvt pathway as a model for selective autophagy.

Autophagy is a highly conserved, ubiquitous process that is responsible for the degradation of cytosolic components in response to starvation. Autophagy is generally considered to be non-selective; however, there are selective types of autophagy that use receptor and adaptor proteins to specifically isolate a cargo. One type of selective autophagy in yeast is the cytoplasm to vacuole targeting (Cvt) pathway. The Cvt pathway is responsible for the delivery of the hydrolase aminopeptidase I to the vacuole; as such, it is the only known biosynthetic pathway that utilizes the core machinery of autophagy. Nonetheless, it serves as a model for the study of selective autophagy in other organisms.

A genomic screen for yeast mutants defective in selective mitochondria autophagy.

Mitophagy is the process of selective mitochondrial degradation via autophagy, which has an important role in mitochondrial quality control. Very little is known, however, about the molecular mechanism of mitophagy. A genome-wide yeast mutant screen for mitophagy-defective strains identified 32 mutants with a block in mitophagy, in addition to the known autophagy-related (ATG) gene mutants. We further characterized one of these mutants, ylr356wDelta that corresponds to a gene whose function has not been identified. YLR356W is a mitophagy-specific gene that was not required for other types of selective autophagy or macroautophagy. The deletion of YLR356W partially inhibited mitophagy during starvation, whereas there was an almost complete inhibition at post-log phase. Accordingly, we have named this gene ATG33. The new mutants identified in this analysis will provide a useful foundation for researchers interested in the study of mitochondrial homeostasis and quality control.