Fresenius, Heidi L; Winter, Jake; Rutter, Jared; Wohlever, Matthew L
description
Evasion of apoptosis is a hallmark of cancer and reactivation of apoptosis is a promising strategy for cancer therapy. Key regulators of apoptosis include the BCL2 family of tail anchored membrane proteins. While there have been significant studies on how BCL2 family proteins are targeted to the outer mitochondrial membrane (OMM), the removal of these proteins from the OMM remains understudied. ATAD1 is a recently discovered AAA+ ATPase that maintains mitochondrial proteostasis by removing tail anchored proteins from the OMM. Here, we report the discovery of ATAD1 as a new negative apoptotic regulator that modulates the mitochondrial concentration of BCL2 family proteins. Using a combination of in vitro reconstitution and cell biology experiments, we demonstrate that ATAD1 directly removes the pro-apoptotic protein BIM from the OMM. Loss of ATAD1 leads to accumulation of BIM on the OMM and renders cancer cells sensitive to proteotoxic stress. ATAD1 is only 40 kb away from the potent tumor suppressor gene PTEN and is co-deleted with PTEN in many cancers. Thus, ATAD1 null cancer cells have a pro-apoptotic vulnerability which can potentially be exploited in cancer treatment.
