Context-defined PHB2 states: an evidence-based framework for receptor-associated signaling, mitochondrial quality control and immune responses

Prohibitin 2 (PHB2) has been linked to mitochondrial inner-membrane organization, mitophagic recognition, receptor-associated signaling and nuclear transcription. Treating these observations as functions of a single uniform protein entity obscures important differences in localization, PHB1 dependence, membrane exposure and partner composition. Here, we use an evidence-based framework to distinguish context-defined PHB2 molecular states according to compartment or membrane topology, native-complex status and accessibility of defined molecular interfaces. Receptor-associated studies involving IGFBP6, grancalcin, SLAMF/B-cell receptor complexes, GALNT14-dependent IGF1R signaling and DDR2-TGFBR2 regulation support stimulus- and cell-restricted PHB2-containing systems, but do not establish a universal PHB2 surface receptor or a common trafficking route. Within mitochondria, crista architecture, respiratory competence and proteostasis are predominantly properties of the PHB1-PHB2 assembly, whereas damage-induced exposure of the PHB2 LC3-interacting region provides a subunit-specific mechanism for mitophagic recognition. PHB2 also contributes at distinct stages of PINK1-Parkin mitophagy, although the upstream PARL-PGAM5-PINK1 effect is less clearly separable from prohibitin-complex function than the mapped LIR-LC3 interaction. Divergent immune outcomes further vary with the mitochondrial cargo being removed and the experimental context: clearance of mitochondria that provide cytosolic mtDNA or other NLRP3-activating signals can limit inflammatory signaling, whereas turnover of MAVS-containing membranes can suppress type I interferon. Post-translational modifications regulate local PHB2 interactions or complex stability, but current evidence does not support a universal modification-driven trafficking program. Mechanistic and pharmacological studies should therefore define the relevant PHB2 state or molecular interface, verify native PHB1-PHB2 complex integrity and measure direct target engagement.