Sorting through the roles of beclin 1 in microglia and neurodegeneration

Abstract

Beclin 1 has a well-established role in regulating autophagy, a cellular degradation pathway. Although the yeast ortholog of beclin 1 (Atg6/Vps30) was discovered to also regulate vacuolar protein sorting nearly 30 years ago, the varied functions of beclin 1 in mammalian cells are only beginning to be sorted out. We recently described a role for beclin 1 in regulating recycling of phagocytic receptors in microglia, a function analogous to that of its yeast ortholog. Microglia lacking beclin 1 have a reduced phagocytic capacity, which impairs clearance of amyloid β (Aβ) in a mouse model of Alzheimer's Disease (AD). Here we summarize these findings and discuss the implications for beclin 1-regulated receptor recycling in neurodegenerative disease.

Figure 1. Beclin 1 recruits the retromer complex to recycle receptors

a) In yeast, hydrolase receptors such as Vps10, bind their cargo in the TGN for delivery to the vacuole. Vps30, the yeast ortholog of beclin 1, and the PI3K complex (containing Vps34 and Vps15) generates PI3P on the endosomal membrane, which recruits the retromer. While the cargo traffics to the vacuole, the retromer recycles the receptor back to the TGN for further rounds of sorting. b) In mammals, cell surface receptors such as the microglial scavenger receptor CD36 bind extracellular cargo and are endocytosed. Beclin 1 and the PI3K rapidly recruit the retromer to the endosome via PI3P production. The retromer then sorts the receptor to a recycling endosome and ultimately back to the cell surface. Meanwhile, cargo is delivered to the lysosome for degradation.