9.B.191 The Endoplasmic Reticulum Retention Receptor (KDELR) Family 

The endoplasmic reticulum (ER)-Golgi system has been studied using biochemical, genetic, electron and light microscopic techniques leading to an understanding of many aspects of trafficking from the ER to the Golgi apparatus (Murshid and Presley 2004). This includes some of the signals and mechanisms for selective retention and retrieval of ER resident proteins and export of cargo proteins. Proteins that leave the ER emerge in 'export complexes' or ER 'exit sites' and accumulate in pleiomorphic transport carriers referred to as VTCs or intermediate compartments. These structures then transit from the ER to the Golgi apparatus along microtubules using the dynein/dynactin motor and fuse with the cis cisterna of the Golgi apparatus. Many proteins (including vSNAREs, ERGIC53/p58 and the KDEL receptor) must cycle back to the ER from pre-Golgi intermediates or the Golgi. Murshid and Presley 2004 considered a   model suggesting that this cycling occurs via 50-nm COPI-coated vesicles and in vivo evidence that suggests  that retrograde trafficking may occur via tubular structures. Intracellular membrane transport involves the coordinated engagement of a series of organelles and molecular machineries that ensure that proteins are delivered to their correct cellular locations.

Due to its central position in the secretory pathway and to the large amounts of signaling molecules associated with it, the Golgi complex plays a role in this regulation. The generation of autonomous signaling by the Golgi complex in response to the arrival of cargo from the endoplasmic reticulum (ER) allows that cargo moving from the ER to the Golgi activates a series of signaling pathways.  This regulatory mechanism is called the Golgi control system (Cancino et al. 2013). A key player in this control system is the KDEL receptor, which  retrieves chaperones back to the endoplasmic reticulum and behaves as a signaling receptor. The KDEL receptor regulates pathways involved in the maintenance of the homeostatic transport apparatus, in particular, of the Golgi complex.

The KDELR determines the specificity of the luminal ER protein retention system and is required for normal vesicular traffic through the Golgi as well as retreval from the Golgi back to the ER. Retrieval of ER luminal proteins from the Golgi is possible via the pH-dependent recognition of a carboxyl-terminal Lys-Asp-Glu-Leu (KDEL) signal in the substrate protein by the KDEL receptor. The crystal structures of the chicken KDEL receptor in the apo ER state and the KDEL-bound Golgi state have been solved (Bräuer et al. 2019). They show a transporter-like architecture that undergoes conformational changes upon KDEL binding with a pH-dependent interaction network crucial for recognition of the carboxyl terminus of the KDEL signal in the target protein. The structures explain how these features create a pH-dependent retrieval system in the secretory pathway (Bräuer et al. 2019).

KDELRs are ubiquitous seven-transmembrane domain proteins encoded by three mammalian genes. They bind to and retro-transport endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Leu (KDEL) sequence or variants thereof (Cela et al. 2022). In doing this, KDELRs participate in the ER quality control of newly synthesized proteins and the unfolded protein response. The binding of KDEL proteins to KDELRs initiate signaling cascades involving three alpha subunits of heterotrimeric G proteins, Src family kinases, protein kinases A (PKAs), and mitogen-activated protein kinases (MAPKs). These signaling pathways coordinate membrane trafficking flows between secretory compartments and control the degradation of the extracellular matrix (ECM), an important step in cancer progression (Cela et al. 2022).