Mitochondrial P-JNK target, SAB (SH3BP5), in regulation of cell death

Abstract

Cell death occurs in various circumstances, such as homeostasis, stress response, and defense, via specific pathways and mechanisms that are regulated by specific activator-induced signal transductions. Among them, Jun N-terminal kinases (JNKs) participate in various aspects, and the recent discovery of JNKs and mitochondrial protein SAB interaction in signal regulation of cell death completes our understanding of the mechanism of sustained activation of JNK (P-JNK), which leads to triggering of the machinery of cell death. This understanding will lead the investigators to discover the modulators facilitating or preventing cell death for therapeutic application in acute or chronic diseases and cancer. We discuss here the mechanism and modulators of the JNK-SAB-ROS activation loop, which is the core component of mitochondria-dependent cell death, specifically apoptosis and mitochondrial permeability transition (MPT)-driven necrosis, and which may also contribute to cell death mechanisms of ferroptosis and pyroptosis. The discussion here is based on the results and evidence discovered from liver disease models, but the JNK-SAB-ROS activation loop to sustain JNK activation is universally applicable to various disease models where mitochondria and reactive oxygen species contribute to the mechanism of disease.

Keywords: JNK-SAB-ROS activation loop; Jun N-terminal kinase; SAB (SH3BP5); SAB-KIM1 peptide; apoptosis; ferroptosis; necrosis; pyroptosis.

FIGURE 1

Topology of SAB and SAB regulation of apoptosis or necrosis via mitochondrial ROS production and sustained P-JNK. Topology of SAB is depicted in the figure. SAB is located at the outer mitochondrial membrane (OMM) with one membrane-spanning sequence. C-terminus of SAB is facing the cytoplasm and has JNK-docking motif (KIM2, dark orange) and JNK phosphorylation sites. N-terminus of SAB is facing the intermembrane space and has the SH3 domain-binding sequence (light orange) which may harbor PTPN6. Stress-induced activated JNK (P-JNK) binding and phosphorylation of OMM protein SAB lead to the release of intramitochondrial protein tyrosine phosphatase PTPN6, which then translocates to inner mitochondrial protein DOK4 where active P-Src is dephosphorylated and inactivated by PTPN6. Activated P-Src maintains the mitochondrial electron transport chain (ETC) activity, and dephosphorylation of Src decreases ETC and increases ROS production, which upregulates ASK1 activation and then MAP2K and JNK activation. The JNK-SAB-ROS feed forward activation loop sustains the JNK activation and incrementally increases ROS production, leading to apoptosis via outer mitochondrial membrane permeabilization (OMMP) or necrosis via increased mitochondrial permeability transition (MPT) depending on the nature of the specific cell death inducer.