The KDEL receptor couples to Gα_q/11to activate Src kinases and regulate transport through the Golgi

Abstract

Membrane trafficking involves large fluxes of cargo and membrane across separate compartments. These fluxes must be regulated by control systems to maintain homoeostasis. While control systems for other key functions such as protein folding or the cell cycle are well known, the mechanisms that control secretory transport are poorly understood. We have previously described a signalling circuit operating at the Golgi complex that regulates intra‐Golgi trafficking and is initiated by the KDEL receptor (KDEL‐R), a protein previously known to mediate protein recycling from the Golgi to the endoplasmic reticulum (ER). Here, we investigated the KDEL‐R signalling mechanism. We show that the KDEL‐R is predicted to fold like a G‐protein‐coupled receptor (GPCR), and that it binds and activates the heterotrimeric signalling G‐protein Gαq/11 which, in turn, regulates transport through the Golgi complex. These findings reveal an unexpected GPCR‐like mode of action of the KDEL‐R and shed light on a core molecular control mechanism of intra‐Golgi traffic.

KDEL Receptors Assist Dengue Virus Exit from the Endoplasmic Reticulum

“…However, results with DENV4 and WNV suggest that additional host proteins are specifically involved in sorting flaviviruses through late secretory compartments and assisting their release from infected cells. In recent years, evidence has accumulated to suggest that, besides their well-established function in retrieving chaperones, KDELR can be activated by cargo to trigger signaling pathways that regulate anterograde and retrograde traffic (Giannotta et al, 2012;Pulvirenti et al, 2008). Specifically, it has been proposed that KDELRs recognize chaperones that are carried by ER vesicles en route to Golgi (Cancino et al, 2013).…”

Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Secretion and Cell Surface Binding Are Modulated by KDEL Receptors

“…In addition to the retrieval function of KDELRs, a recent report demonstrated a signaling function via a G-protein-coupled receptor-like fold in the KDEL receptors (36). The KDELR has also been shown to modulate activity of the p38 mitogenactivated protein kinases (MAPK and c-Jun N-terminal kinases (JNKs)), which are important critical regulators of cell differentiation and survival (37).…”

RNA interference mediated knockdown of the KDEL receptor and COPB2 inhibits digestion and reproduction in the parasitic copepod Lepeophtheirus salmonis

“…It is a seven transmembrane receptor predicted to fold like a G-protein coupled receptor (GPCR) (Capitani and Sallese, 2009). Recently, KDELR was also shown to regulate protein transport in the Golgi (Pulvirenti et al, 2008), and to act like a GPCR, activating Golgi G q/11 G-proteins that initiate a signalling pathway to regulate secretory traffic (Giannotta et al, 2012). Thus, KDELR plays a dual role, firstly sorting and binding of proteins with a KDEL sequence and secondly by initiating regulatory pathways of the vesicular transport system.…”