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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Linfei Niu1
  • Linfei Niu2
  • Xiaoqing Wang1
  • Xiaoqing Wang2
  • Xiwei Wang3
  • Jing Liu1
  • Jing Liu4
  • Chunyan Liu1
  • Chunyan Liu2
  • Chunyan Liu5
  • Zhengbin Chai4
5 affiliations
  1. 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
  2. 2Jinan Clinical Research Center for Tissue Engineering Skin Regeneration and Wound Repair, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
  3. 3Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
  4. 4Department of Clinical Laboratory Medicine, Public Health Clinical Center Affiliated to Shandong University, Jinan, Shandong, China
  5. 5Department of Plastic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{niu2026contextdefined,
  title = {{Context-defined PHB2 states: an evidence-based framework for receptor-associated signaling, mitochondrial quality control and immune responses}},
  author = {Linfei Niu and Linfei Niu and Xiaoqing Wang and Xiaoqing Wang and Xiwei Wang and Jing Liu and Jing Liu and Chunyan Liu and Chunyan Liu and Chunyan Liu and Zhengbin Chai},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = nov,
  doi = {10.3389/fimmu.2026.1984641},
  url = {https://doi.org/10.3389/fimmu.2026.1984641},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Context-defined PHB2 states: an evidence-based framework for receptor-associated signaling, mitochondrial quality control and immune responses
AU  - Linfei Niu
AU  - Linfei Niu
AU  - Xiaoqing Wang
AU  - Xiaoqing Wang
AU  - Xiwei Wang
AU  - Jing Liu
AU  - Jing Liu
AU  - Chunyan Liu
AU  - Chunyan Liu
AU  - Chunyan Liu
AU  - Zhengbin Chai
PY  - 2026
DA  - 2026/11/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1984641
UR  - https://doi.org/10.3389/fimmu.2026.1984641
AB  - 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.
SN  - 1664-3224
ER  -