Molecular mechanism of PHB2 action. On the surface of cells, PHB2 acts as a receptor for DENV-2 and facilitates the entry of DENV-2 into insect cells. In the mitochondria, PHB2 interacts with MAVS, which requires a bridging protein called CLPB, and activates the innate immune response. Upon cell stress, BIF-1 translocates to mitochondria and binds PHB2, resulting in apoptosis. PHB2 binds the autophagosomal membrane-associated protein LC3 and mediates mitophagy. In the absence of the brefeldin A-inhibited guanine nucleotide-exchange protein-3 (BIG3), \beta-estradiol treatment led to increased PHB2 nuclear translocation and reduction of estrogen-dependent transcription. On the other hand, in the presence of BIG3, PHB2/REA binds to BIG3 in the cytoplasm and its nuclear translocation is inhibited, resulting in the constitutive activation of the ER signaling. In the nuclear, PHB2 interacts with hnRNPA1 to inhibit hnRNPA1-mediated pre-PKM mRNA splicing, and fine-tuning glucose metabolic reprogramming.