The Role of BiP Retrieval by the KDEL Receptor in the Early Secretory Pathway and its Effect on Protein Quality Control and Neurodegeneration

Abstract

Protein quality control in the early secretory pathway is a ubiquitous eukaryotic mechanism for adaptation to endoplasmic reticulum (ER) stress. An ER molecular chaperone, immunoglobulin heavy chain-binding protein (BiP), is one of the essential components in this process. BiP interacts with nascent proteins to facilitate their folding. BiP also plays an important role in preventing aggregation of misfolded proteins and regulating the ER stress response when cells suffer various injuries. BiP is a member of the 70-kDa heat shock protein (HSP70) family of molecular chaperones that resides in the ER. Interaction between BiP and unfolded proteins is mediated by a substrate-binding domain and a nucleotide-binding domain for ATPase activity, leading to protein folding and maturation. BiP also possesses a retrieval motif in its carboxyl terminal. When BiP is secreted from the ER, the Lys-Asp-Glu-Leu (KDEL) receptor in the post-ER compartments binds with the carboxyl terminal KDEL sequence of BiP and returns BiP to the ER via coat protein complex I (COPI) vesicular transport. Although yeast studies showed that BiP retrieval by the KDEL receptor is not essential in single cells, it is crucial for multicellular organisms, where some essential proteins require retrieval to facilitate folding and maturation. Experiments in knock-in mice expressing mutant BiP with the retrieval motif deleted revealed a unique role of BiP retrieval by the KDEL receptor in neuronal development and age-related neurodegeneration.

RareRELNvariants affect Reelin-DAB1 signal transduction in autism spectrum disorder

“…Indeed, impaired Reelin folding and secretion were observed in a mouse model lacking binding immunoglobulin protein (BiP), one of the most abundant ER chaperones (Jin, Komita, & Aoe, ; Mimura et al., ). Also, altered Reelin processing and impaired release were shown in the Reln Orleans mice (which lacks the C‐terminal half of the eighth Reelin repeat as well as the C‐terminal region of the protein; de Bergeyck et al., ), in a mouse model of temporal lobe epilepsy (Duveau, Madhusudan, Caleo, Knuesel, & Fritschy, ; Tinnes et al., ) and, more recently, in patients with autosomal‐dominant lateral temporal epilepsy (ADLTE) carrying missense heterozygous variants located within subrepeats 1B, 7A, and 8A of Reelin (Dazzo et al., ).…”

“…Indeed, impaired Reelin folding and secretion were observed in a mouse model lacking binding immunoglobulin protein (BiP), one of the most abundant ER chaperones (Jin, Komita, & Aoe, 2017;Mimura et al, 2008). Also, altered Reelin processing and impaired release were shown in the Reln Orleans mice (which lacks the C-terminal half of the eighth Reelin repeat as well as the C-terminal region of the protein;…”

Conflicting Actions of Inhalational Anesthetics, Neurotoxicity and Neuroprotection, Mediated by the Unfolded Protein Response

“…These proteins are subsequently translocated to the ER membrane and undergo folding to become functional proteins with mature structures; this process involves significant interaction with molecular chaperones in the ER, including binding immunoglobulin protein (BiP). Subsequently, these proteins are transported to the secretory pathway to carry out their functional role; for example, as such as cell surface receptors or secretory proteins [24,25]. ER stresses, such as hypoxia, ischemia, malnutrition, or mutation, initiates an adaptive response referred to as the unfolded protein response (UPR) [26].…”

“…BiP is returned back to the ER by coat protein I (COPI) vesicles [44]. Mutant BiP lacks the KDEL sequence and exhibits impairment in terms of ER function [25]. Homozygous mutant Bip mice die on the first day after birth because their ability to synthesize pulmonary surfactant is impaired [45].…”

A recombinant cholera toxin b subunit variant (CTB-KDEL) exhibits unique colon mucosal healing effects that have therapeutic implications for inflammatory bowel disease.

“…What is unknown is if CTB-KDEL also directly interacts with IRE1 to displace BiP or if the binding of the KDELR alone is sufficient to induce BiP dissociated from IRE1 and subsequent downstream signaling. There is also a possibility that the UPR response is in part attributed to competition between CTB-KDEL and BiP for KDELR, as BiP relies on KDELR for retrieval back to the ER [121,[190][191][192]. In this regard, the role of KDELR in CTB-KDEL-induced epithelial repair activity warrants further investigation.…”