Inorganic polyphosphate controls cyclophilin B-mediated collagen folding in osteoblast-like cells.

Evidence is emerging that inorganic polyphosphate (polyP) is a fundamental molecule involved in a wide range of biological processes. In higher eukaryotes, polyP is abundant in osteoblasts but questions remain as to its functions. Here, we find that polyP is particularly enriched in endoplasmic reticulum (ER) where it colocalizes with cyclophilin B (CypB) using osteoblastic SaOS-2 model cell line. PolyP binds directly and specifically to CypB, inhibiting its peptidyl-prolyl cis-trans isomerase activity which is critical for collagen folding. PolyP sequestration by spermine and ER-specific polyP reduction by polyphosphatase expression in cells reduced collagen misfolding and confirmed that endogenous polyP acts as a molecular control of CypB-mediated collagen folding. We propose that polyP is a previously unrecognized critical regulator of protein homeostasis in ER.