Using a yeast two-hybrid system, we screened a human brain cDNA library for possible interacting proteins with the C-terminal cytosolic tail of the β-secretase β-amyloid protein converting enzyme (BACE)1. This identified seven potential candidates, including the brain-specific type II membrane protein BRI3. Co-localization and co-immunoprecipitation experiments confirmed that BACE1 and BRI3 co-localize and interact with each other via the cytosolic tail of BACE1. Furthermore, pulse and pulse-chase analyses revealed that the pro-protein convertases furin, and to a lesser extent PC7 and PC5A, process BRI3 into a C-terminal secreted ∼ 4-kDa product. Thus, furin efficiently processes both pro-BACE1 and its novel interacting protein pro-BRI3.