The proper functioning of all eukaryotic cells depends on their ability to use a lysosomal pathway known as autophagy to degrade self-constituents. Genetic screens in yeast identified a set of evolutionarily conserved genes that are required for the autophagy pathway. Our laboratory identified the first mammalian autophagy gene, beclin 1, which encodes a component of a class III PI3 kinase complex that mediates the localization of other autophagy proteins to 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. We found that beclin 1–dependent autophagy plays a role in the development of evolutionarily diverse organisms, in negative growth control and tumor suppression, in innate immunity against intracellular pathogens, in protection against aging and neurodegenerative disorders, and in cell death regulation. We demonstrated that decreased host Beclin 1–dependent autophagy (as a result of genetic mutations, epigenetic factors, or inhibition by viral virulence factors) contributes to the pathogenesis of cancer, aging, Alzheimer’s disease, and fatal herpes simplex virus encephalitis. We also found that autophagy plays an essential role in providing the energy necessary for dying cells to be cleared efficiently by their neighbors, which suggests that defective autophagy may also contribute to inflammatory and autoimmune diseases.

In addition to our work with Beclin 1 and other autophagy “execution” proteins, we also defined a role for evolutionarily conserved signaling pathways in the positive regulation of autophagy (e.g., the stress-induced eIF2α kinase signaling pathway) and in the negative regulation of autophagy (e.g., the oncogenic insulin-like signaling pathway). We have demonstrated that Bcl-2 family members, proteins previously believed to function primarily as negative regulators of apoptosis, also play a critical role in the negative regulation of autophagy through inhibitory interactions with Beclin 1. We have shown that the interaction of Bcl-2 and Beclin 1 represents a central switch for turning autophagy on or off in response to cellular stress, and this is controlled by Bcl-2 phosphorylation by the stress-activated signaling molecule, c-Jun N-terminal protein kinase 1.

Our ongoing research is focused on defining how Beclin 1 functions in autophagy at the biochemical, cell biology, and molecular levels, and how cellular Bcl-2 proteins and viral virulence factors inhibit Beclin 1–dependent autophagy. We are using these insights and genetic knockout approaches in cultured cells and model organisms to determine how autophagy functions in tumor suppression, life span extension, cell death regulation, development, antiviral immunity, and autoimmunity.

We are also investigating the role that Beclin 1 and other autophagy defects may play in patients with epithelial cell malignancies (breast and lung carcinoma) and lymphomas; in viral infections such as HIV, herpes simplex encephalitis, and Kaposi’s sarcoma; and in autoimmune diseases, such as systemic lupus erythematosis (SLE). We hope that by defining how Beclin 1 functions in autophagy, how Beclin 1 function is regulated, and how defects in Beclin 1 and autophagy contribute to disease, we will be able to design pharmacological agents that can augment autophagy in patients, extend life span, and aid in the treatment of human ailments such as cancer, neurodegenerative disorders, autoimmune diseases, and infectious diseases.