Prohibitin: A Novel Molecular Player in KDEL Receptor Signalling

Abstract

The KDEL receptor (KDELR) is a seven-transmembrane-domain protein involved in retrograde transport of protein chaperones from the Golgi complex to the endoplasmic reticulum. Our recent findings have shown that the Golgi-localised KDELR acts as a functional G-protein-coupled receptor by binding to and activating Gs and Gq. These G proteins induce activation of PKA and Src and regulate retrograde and anterograde Golgi trafficking. Here we used an integrated coimmunoprecipitation and mass spectrometry approach to identify prohibitin-1 (PHB) as a KDELR interactor. PHB is a multifunctional protein that is involved in signal transduction, cell-cycle control, and stabilisation of mitochondrial proteins. We provide evidence that depletion of PHB induces intense membrane-trafficking activity at the ER–Golgi interface, as revealed by formation of GM130-positive Golgi tubules, and recruitment of p115, β-COP, and GBF1 to the Golgi complex. There is also massive recruitment of SEC31 to endoplasmic-reticulum exit sites. Furthermore, absence of PHB decreases the levels of the Golgi-localised KDELR, thus preventing KDELR-dependent activation of Golgi-Src and inhibiting Golgi-to-plasma-membrane transport of VSVG. We propose a model whereby in analogy to previous findings (e.g., the RAS-RAF signalling pathway), PHB can act as a signalling scaffold protein to assist in KDELR-dependent Src activation.

Vascular targeted nanotherapeutic approach for obesity treatment

“…It is expressed in various cellular compartments including the mitochondria, nucleus, ER, the Golgi complex, endosomes, and plasma membrane. [76][77][78] Most of the cellular functions mentioned above are credited to the mitochondrial and nuclear PHB. The mitochondrial PHB sustains the livelihood of the cell by keeping the mitochondrial function intact, while the nuclear PHB regulates cellular transcriptional activity.…”

“…PHB was reported to be overexpressed in obesity, 16 cancer, and diabetes and could serve as a potential biomarker for therapeutic intervention. 74,78,79 Molecules that bind to PHB in various diseases are also highlighted in Table 1; they include AHP, 16 flavaglines (FLs), 80 and miR-361. 77 These ligands were used to deliver therapy or gene silencing molecules to PHB for the treatment of diseases.…”

“…FLs (FL3 and FL37) exerts their cytoprotective effects by binding to molecular targets such as PHB and translation initiation factor eIF4A. 78,81 The FLs have selective toxicity toward colon cancer cells, bind to PHB in in vitro (Caco-2 BBE cells) and in vivo (chemically induced colitis in mice) models of inflammatory bowel diseases, and inhibit cancer cell proliferation. 78 PHB is also upregulated in colorectal cancer (CRC) stages I-III.…”

“…78,81 The FLs have selective toxicity toward colon cancer cells, bind to PHB in in vitro (Caco-2 BBE cells) and in vivo (chemically induced colitis in mice) models of inflammatory bowel diseases, and inhibit cancer cell proliferation. 78 PHB is also upregulated in colorectal cancer (CRC) stages I-III. 82 Targeting PHB with AHP containing a pro-apoptotic (KLA) molecule inhibited proliferation of Caco-2 colon cancer cells.…”

“…Thus, therapeutic strategies that target PHB may unfold the molecular mechanisms and pathogenesis of these diseases. 16,77,78,87 Targeted nanotherapy is currently being explored as a potential treatment for obesity in a rodent and non-human primate models of diet-induced obesity, by targeting the vascular system that supports the growth of hypertrophic adipocytes. 17,18,78,85 Disease-associated biomarkers play a crucial role in targeted drug delivery, tissue imaging, and diagnostics.…”