Progesterone receptor membrane component 1 facilitates Cal plus signal amplification between endosomes and the endoplasmic reticulum

Membrane contact sites (MCSs) between endosomes and the endoplasmic reticulum (ER) are thought to act as specialized trigger zones for Cal+ signaling, where local Cal+ released via endolysosomal ion channels is amplified by ER Cal+-sensitive Cal+ channels into global Cal+ signals. Such amplification is integral to the action of the second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, functional regulators of inter-organellar Cal+ crosstalk between endosomes and the ER remain poorly defined. Here, we identify progesterone receptor membrane component 1 (PGRMC1), an ER transmembrane protein that undergoes a unique hemedependent dimerization, as an interactor of the endosomal two pore channel, TPC1. NAADP-dependent Cal+ signals were potentiated by PGRMC1 overexpression through enhanced functional coupling between endosomal and ER Cal+ stores and inhibited upon PGRMC1 knockdown. Point mutants in PGMRC1 or pharmacological manipulations that reduced its interaction with TPC1 were without effect. PGRMC1 therefore serves as a TPC1 interactor that regulates ER-endosomal coupling with functional implications for cellular Cal+ dynamics and potentially the distribution of heme.