KDEL receptor is a cell surface receptor that cycles between the plasma membrane and the Golgi via clathrin-mediated transport carriers

Jia, Jie; Yue, Xihua; Zhu, Lianhui; Jing, Shuaiyang; Wang, Yijing; Gim, Bopil; Qian, Yi; Lee, Intaek

doi:10.1007/s00018-020-03570-3

Cited by 27 publications

(49 citation statements)

References 32 publications

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“…The retention signals in both E1 and E2 of pestiviruses most likely belong to the former. KDEL as a retrieval signal returns the cargo from the Golgi apparatus to the ER via a well-characterized specific receptor ( 45 – 48 ). Like many viral ( 41 ) envelope proteins, the pestiviral glycoproteins do not contain one of these known retention signals.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Membrane Topology and Retention Signal of Pestiviral Glycoprotein E1

Radtke

Tews

et al. 2021

J Virol

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Pestiviruses are members of the family Flaviviridae, a group of enveloped viruses that bud at intracellular membranes. Pestivirus particles contain three glycosylated envelope proteins, Erns, E1 and E2. Among them, E1 is the least characterized concerning both biochemical features and function. E1 from bovine viral diarrhea virus (BVDV) strain CP7 was analyzed with regard to its intracellular localization and membrane topology. Here, it is shown that even in the absence of other viral proteins, E1 is not secreted or expressed at the cell surface, but localizes predominantly in the ER. Using engineered chimeric TM domains with sequences from E1 and vesicular stomatitis virus G protein, the E1 ER-retention signal could be narrowed down to six fully conserved polar residues in the middle part of the transmembrane domain of E1. Retention was observed even when several of these polar residues were exchanged for alanine. Mutations with a strong impact on E1 retention prevented recovery of infectious viruses when tested in the viral context. Analysis of the membrane topology of E1 before and after the signal peptide cleavage via a selective permeabilization and an in vivo labelling approach revealed that mature E1 is a typical type I transmembrane protein with a single span transmembrane anchor at its C-terminus whereas it adopts a hairpin-like structure with the C-terminus located in the ER lumen when the pre-cleavage situation is mimicked by blocking the cleavage site between E1 and E2. Importance The shortage of specific antibodies against E1 making detection and further analysis of E1 difficult, resulted in a lack of knowledge on E1 compared to Erns and E2 with regard to biosynthesis, structure and function. It is known that pestiviruses bud intracellularly. Here, we show that E1 contains its own ER retention signal: six fully conserved polar residues in the middle part of the TM domain are shown to be the determinants for ER retention of E1. Moreover, those six polar residues could serve as a functional group that intensely affect the generation of infectious viral particles. In addition, the membrane topology of E1 has been determined. In this context, we also identified dynamic changes in membrane topology of E1 with the carboxy-terminus located on the luminal side of the ER in the pre-cleavage state and relocation of this sequence upon signal peptidase cleavage. Our work provides the first systematic analysis of the pestiviral E1 protein with regard to its biochemical and functional characteristics.

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Section: Discussionmentioning

confidence: 99%

Characterization of Membrane Topology and Retention Signal of Pestiviral Glycoprotein E1

Radtke

Tews

et al. 2021

J Virol

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“…Given their role in trafficking and autophagy, KDEL receptors may also promote the degradation and removal of misfolded proteins during ER stress. KDEL receptors traffic to the cell surface basally and under stress conditions, where they can interact with ERS ligands to form clusters and potentially promote signaling [ 21 , 23 , 24 , 94 , 95 ]. The presence of KDEL receptors at the cell surface may function to retrieve secreted ERS proteins from the extracellular space.…”

Section: Discussionmentioning

confidence: 99%

The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein misfolding and activation of the unfolded protein response (UPR). Additionally, ER resident proteins are secreted from the cell by overwhelming the KDEL receptor retrieval pathway. Recent data show that KDEL receptors are also activated during the UPR through the IRE1/XBP1 signaling pathway as an adaptive response to cellular stress set forth to reduce the loss of ER resident proteins. This review will discuss the emerging connection between UPR activation and KDEL receptors as it pertains to ER proteostasis and disease states.

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“…This evidence of an interaction with KDEL receptors warrants further study to gain a complete picture of the KDEL receptor retrieval pathway and how ERS differences or KDEL receptor isoforms may influence protein trafficking. Furthermore, the understanding of the presence and action of KDEL receptors on the plasma membrane may provide insight into the mechanism of action of ERS containing proteins that are secreted from the cell following ER calcium depletion ( Jia et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Computational Modeling of C-Terminal Tails to Predict the Calcium-Dependent Secretion of Endoplasmic Reticulum Resident Proteins

Xie

Verma

et al. 2021

Front. Chem.

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The lumen of the endoplasmic reticulum (ER) has resident proteins that are critical to perform the various tasks of the ER such as protein maturation and lipid metabolism. These ER resident proteins typically have a carboxy-terminal ER retention/retrieval sequence (ERS). The canonical ERS that promotes ER retrieval is Lys-Asp-Glu-Leu (KDEL) and when an ER resident protein moves from the ER to the Golgi, KDEL receptors (KDELRs) in the Golgi recognize the ERS and return the protein to the ER lumen. Depletion of ER calcium leads to the mass departure of ER resident proteins in a process termed exodosis, which is regulated by KDELRs. Here, by combining computational prediction with machine learning-based models and experimental validation, we identify carboxy tail sequences of ER resident proteins divergent from the canonical “KDEL” ERS. Using molecular modeling and simulations, we demonstrated that two representative non-canonical ERS can stably bind to the KDELR. Collectively, we developed a method to predict whether a carboxy-terminal sequence acts as a putative ERS that would undergo secretion in response to ER calcium depletion and interacts with the KDELRs. The interaction between the ERS and the KDELR extends beyond the final four carboxy terminal residues of the ERS. Identification of proteins that undergo exodosis will further our understanding of changes in ER proteostasis under physiological and pathological conditions where ER calcium is depleted.

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KDEL receptor is a cell surface receptor that cycles between the plasma membrane and the Golgi via clathrin-mediated transport carriers

Cited by 27 publications

References 32 publications

Characterization of Membrane Topology and Retention Signal of Pestiviral Glycoprotein E1

Characterization of Membrane Topology and Retention Signal of Pestiviral Glycoprotein E1

The Function of KDEL Receptors as UPR Genes in Disease

Computational Modeling of C-Terminal Tails to Predict the Calcium-Dependent Secretion of Endoplasmic Reticulum Resident Proteins

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