The KDEL Receptor Modulates the Endoplasmic Reticulum Stress Response through Mitogen-activated Protein Kinase Signaling Cascades

Abstract

The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted ␣-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.

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

“…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). KDELRs are also implicated in regulating autophagy, where overexpression of KDELR promoted clearance of neurodegenerative disease-related proteins in cell culture (38).…”

p38 Mitogen-Activated Protein Kinase is Involved in Endoplasmic Reticulum Stress-Induced Cell Death and Autophagy in Human Gingival Fibroblasts

“…11) In contrast, ER-stress activation of p38 signaling serves also as survival signal 12) since p38 was shown to be necessary for the survival to ER-stress both in HeLa human cervical carcinoma cells 13) and Saccharomyces cerevisiae. 14) In ER stress-signaling pathways, p38MAPK-associated signaling/physiological roles are necessary to be studied.…”

Quality Control in the Early Secretory Pathway Plays Significant Roles in vivo

“…In addition to retrieval, the recognition of the KDEL sequence of BiP (and other KDEL proteins) by the KDEL receptor leads to signal transduction. The activation of the KDEL receptor may trigger subsequent activation of signaling molecules such as ARF1GAP (Yamamoto et al, 2001), src (Bard et al, 2003), protein kinase A (Cabrera et al, 2003), and mitogen-activated protein kinases (Yamamoto et al, 2003). Chronic morphine administration may cause altered signal transduction through persistent MOR activation.…”

“…These features were consistent with programmed cell death by ER stress, suggesting that the retrieval of BiP and misfolded proteins from post-ER compartments by the KDEL receptor played a significant role in the ER stress response. When retrieval was limited, the susceptibility to ER stress might be increased (Yamamoto et al, 2003).…”

“…We examined how the KDEL receotor-ER chaperone retrieval system participates in ER stress response by using an expression of a mutant KDEL receptor that lacks the ability for ligand recognition. The impairment of retrieval by the KDEL receptor led to a mis-sorting of BiP, an ER chaperone that had a retrieval signal from the early secretory pathway, which induced an increase in susceptibility to ER stress in HeLa cells (Yamamoto et al, 2003).…”