Research

A falsely colored electron micrograph of a herpes simplex virus-infected mouse neuron showing an autophagosome that is degrading herpes simplex virions (viral constituents are colored pink)


A ductal carcinoma in situ lesion in the mammary gland of a 9 month-old female beclin 1 heterozygote-deficient mouse

The proper functioning of all eukaryotic cells depends on their ability to use a lysosomal pathway known as autophagy to degrade self-constituents. Our laboratory identified the mammalian essential autophagy protein, Beclin 1, as a novel Bcl-2-interacting protein. Posttranslational modifications of Beclin 1, regulation of its subcellular localization, and regulation of its binding to other proteins play a crucial role in determining the activity of the Beclin 1-containing class III phosphatidylinositol 3-kinase protein complex that is essential for formation of the autophagosomal membrane.

Using a series of genetic, cell biology, biochemical, and molecular approaches in model organisms ranging from yeast to worms to mice, we have uncovered several important roles that beclin 1 and the autophagy pathway play in normal physiology and in protection against disease, including metazoan development, tumor suppression, innate immunity against intracellular pathogens, lifespan extension, apoptotic corpse clearance, cell death regulation, protection against neurodegenerative diseases, and exercise-induced beneficial effects on glucose metabolism.

We have identified several regulatory mechanisms of autophagy, including a role for the eIF2α kinase signaling pathway in autophagy induction, and the insulin-like signaling pathway in autophagy inhibition. We have shown that Beclin 1 function and autophagy are inactivated by several oncogenes, including Bcl-2, the serine/threonine kinase Akt, and the oncogenic epidermal growth factor receptor (EGFR) tyrosine kinase; by the Golgi-associated protein GAPR-1; and by viral virulence proteins such as HSV-1 encoded ICP34.5, and oncogenic gammaherpesvirus-encoded Bcl-2-like proteins.

Other recent areas of focus include the identification and characterization of a set of gene products required for selective forms of autophagy; characterization of a newly described Na+,K+-ATPase-dependent cell death pathway (autosis) induced by excessive autophagy; characterization of a newly described autophagy gene, beclin 2, that also functions in the endolysosomal turnover of G protein-coupled receptors and acts to prevent diabetes and obesity in mice; and development of new autophagy-inducing peptides (derived from Beclin 1) that may have potential beneficial effects in the treatment of certain neurodegenerative, infectious, and metabolic diseases.

Our future research will continue to use a combination of biochemical, cell biological and genetic approaches to further delineate the molecular regulation of Beclin 1 and Beclin 2 function, and the molecular mechanisms by which Beclin 1 and Beclin 2 and other components of the general and selective autophagy pathways protect against cancer, infectious diseases, aging, and metabolic disorders. In parallel, we will investigate the mechanisms by which excessive autophagy leads to autosis, and the roles of autosis in different pathophysiological conditions. We hope that by defining the roles of altered autophagy in disease we will be able to develop new strategies to modulate the process that can have an impact on clinical medicine.


Physiological levels of autophagy (shaded region of center graph) are essential for normal cellular homeostasis, and the absence of autophagy genes (shaded region of left graph) increases cell death during nutrient deprivation and other forms of cellular stress. In contrast, excessive, non-physiological levels of autophagy (shaded region of right graph) promote autophagy gene-dependent cell death. The relative amounts of Beclin 1 and Bcl-2 (or perhaps other Bcl-2 family members) complexed with each other within a cell govern the threshold for transition from cell homeostasis (center graph) to cell death (right graph).