UNIQUE N-TERMINUS OF HUMAN BID ISOFORM-1 TARGETS MITOCHONDRIA

Abstract

Apoptosis is a form of programmed cell death that plays an important role during embryonic development and for maintaining homeostasis of the human body by removing damaged, aged or unwanted cells. The BCL-2 family of proteins are key regulators of apoptosis and share BCL-2 homology (BH) motifs. BCL-2 homologs and BH3-only proteins exert pro- and anti-apoptotic functions and interact with each other to form a complex network that regulates apoptosis. Their interactions are regulated by a third group of proteins, the BH3-only proteins. A key BH3-only protein is the pro-apoptotic protein BID, which must be activated to kill cells, typically by caspase cleavage. BID promotes cell death by competitively inhibiting anti-death BCL-2 family proteins, by directly activating pro-apoptotic BCL-2 family proteins, and was recently reported to directly permeabilize mitochondrial outer membranes similar to Bax (pro-apoptotic BCL-2 homolog). However, very little is known about the function of BID prior to caspase cleavage. BID is thought to function as a sensor of DNA damage leading to cell death, and may have non-apoptotic functions such as participating in lipid and DNA damage signaling. In this thesis, I sought to investigate the function of extra-long human isoform 1 of BID (BIDEL) in mitochondria, focusing on the localization and mitochondrial targeting mechanism of BIDEL. We found that the unique N-terminal sequence of BIDEL plays an important role in mitochondrial localization, and that a subset of arginine residues are critical for this function.