Lost in translocation: the functions of the 18-kD translocator protein

• The 3D structures of mammalian TSPO and of two bacterial TspOs provided unique insights into this class of TM proteins.
• Despite being dispensable for survival in mice, TSPO may be relevant as a disease or disease-modifying gene.
• In vitro and in vivo data suggest a role of TSPO in regulating cellular energy homeostasis.
• TSPO-null-background animals are useful to assess target selectivity and off-target effects of TSPO-binding drugs.

Research spanning nearly four decades has assigned to the translocator protein (18 kDa) (TSPO) a critical role, among others, in the mitochondrial import of cholesterol, the subsequent steps of (neuro)steroid production, and systemic endocrine regulation, with implications for the pathophysiology of immune, inflammatory, neurodegenerative, and psychiatric as well as neoplastic diseases. Recent knockout studies in mice unexpectedly report normal or latent phenotypes, raising doubts about the protein's role in steroidogenesis and other previously postulated functions and challenging the validity of earlier data on the selectivity of TSPO-binding drugs. Here we provide a synthesis of the current debate from a structural and molecular biology perspective, discuss the limits of inference in loss-of-function (gene knockout) studies, and suggest new functions of TSPO.