An A-kinase anchoring protein (ACBD3) coordinates traffic-induced PKA activation at the Golgi

KDEL receptor (KDELR) is a key protein that recycles escaped endoplasmic reticulum (ER) resident proteins from the Golgi apparatus back to the ER and maintains a dynamic balance between these two organelles in the early secretory pathway. Studies have shown that this retrograde transport pathway is partly regulated by two KDELR-interacting proteins, acyl-CoA-binding domain-containing 3 (ACBD3), and cyclic AMP-dependent protein kinase A (PKA). However, whether Golgi-localized ACBD3, which was first discovered as a PKAanchoring protein in mitochondria, directly interacts with PKA at the Golgi and coordinates its signaling in Golgi-to-ER traffic has remained unclear. In this study, we showed that the GOLD domain of ACBD3 directly interacts with the regulatory subunit II (RII) of PKA and effectively recruits PKA holoenzyme to the Golgi. Forward trafficking of proteins from the ER triggers activation of PKA by releasing the catalytic subunit from RII. Furthermore, we determined that depletion of ACBD3 reduces the Golgi fraction of RII, resulting in moderate, but constitutive activation of PKA and KDELR retrograde transport, independent of cargo influx from the ER. Taken together, these data demonstrate that ACBD3 coordinates the protein secretory pathway at the Golgi by facilitating KDELR/PKA-containing protein complex formation.

Automated summary

KDEL receptor (KDELR) is necessary for recycling ER resident proteins from the Golgi apparatus back to the ER, thus maintaining the balance between these two organelles. ACBD3 and PKA have been shown to regulate this process, but their interaction and coordination at the Golgi have not been fully understood. In this study, it was revealed that ACBD3 directly interacts with the regulatory subunit II (RII) of PKA at the Golgi and recruits PKA to this organelle. Depletion of ACBD3 leads to constitutive activation of PKA and increased retrograde transport of KDELR. These findings highlight the role of ACBD3 in coordinating protein secretion at the Golgi.