The Function of KDEL Receptors as UPR Genes in Disease

Wires, Emily S.; Kennedy, Lacey M.; Harvey, Brandon K.

doi:10.3390/ijms22115436

Cited by 14 publications

(17 citation statements)

References 98 publications

(140 reference statements)

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“…44 Most ER stress-responsive proteins are present in the ER in relatively high amounts and are often considered to exert their activities exclusively in the lumen of the ER owing to a carboxy-terminal ER retention sequence. 48 In addition to ER localization, PDIA4 is located in both the cytoplasm and cell surface and in extracellular spaces (i.e., it is secreted). 23 PDIA4 secretion is induced by its overexpression.…”

Section: Discussionmentioning

confidence: 99%

PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue

Chien

Chen

et al. 2022

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Increasing evidence supporting a causal link between obesity and endoplasmic reticulum (ER) stress in adipose tissue is being reported. Protein disulfide isomerase 4 (PDIA4) is a novel ER chaperone involved in the pancreatic β‐cells pathogenesis in diabetes. However, the role of PDIA4 in obesity progression remains poorly understood. To assess the relationship between PDIA4, adiponectin, and metformin, we used the palmitate‐induced inflammation in hypertrophic adipocytes and the high‐fat diet‐induced obesity mouse model. Our results revealed that palmitate‐induced hypertrophic adipocytes exhibit obesity‐associated conditions such as increased lipid accumulation, inflammation, and reduced glucose uptake. Pharmacological and genetic inhibition of PDIA4 significantly reverses these obesity‐associated conditions in adipocytes. PDIA4 mechanistically promotes obesity progression via adiponectin downregulation. Furthermore, metformin modulates PDIA4 and adiponectin expression and improves obesity‐associated conditions in both in vitro adipocytes and in vivo mouse models. Serum PDIA4 concentrations are also associated with body mass index, adiponectin, triglycerides, and inflammatory cytokines in humans. This is the first study demonstrating that PDIA4 modulates adipocytes by downregulating adiponectin. Moreover, metformin may serve as a potential therapeutic for preventing obesity via PDIA4‐targeting.

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Section: Discussionmentioning

confidence: 99%

PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue

Chien

Chen

et al. 2022

BioFactors

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“…In recent years, numerous studies have sought to elucidate the roles of KDELRs in mammalian cell physiology, and their possible involvement in human diseases [ 1 , 2 , 3 , 20 ].…”

Section: Physiological and Pathological Cell Functions Of Kdel Receptorsmentioning

confidence: 99%

“…KDELRs contribute to the maintenance of ER homeostasis and quality control of the ER primarily through the recovery of ER-resident proteins [ 34 , 35 ], but also by participating in the UPR [ 2 ], a cell reaction triggered by a wide array of cell stresses leading to the impairment of protein folding. Cells use three stress sensors, namely protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6), located on ER membranes, to monitor homeostasis and activate a complex signaling and transcription program aimed at coping with stresses.…”

Section: Physiological and Pathological Cell Functions Of Kdel Receptorsmentioning

confidence: 99%

“…The role of KDELR in diabetes has not yet been elucidated; its association with the disease is based on receptor overexpression [ 52 , 53 ], its contribution to UPR [ 2 ], and its interaction with PHB and MANF [ 31 , 59 ]. It is also worthwhile to note that the IRE1/XBP1 pathway appears to be involved in insulin metabolism in pancreatic cells [ 67 ] while PHB, a scaffold protein that assists in the activation of KDELR-dependent Src for the regulation of membrane trafficking [ 31 ], induces diabetes in transgenic mice [ 68 , 69 ].…”

Section: Involvement Of Kdelrs In Human Diseasesmentioning

confidence: 99%

“…KDEL receptors (KDELRs) are seven-transmembrane-domain proteins primarily involved in the retrieval of endoplasmic reticulum (ER)-resident proteins from post-ER compartments to the ER lumen; this is functionally important to the maintenance of proteostasis in the ER [ 1 , 2 , 3 ]. KDELRs were first described in yeast by Pelham’s lab, which identified two genes, ERD1 and ERD2, required for the retention within cells of a number of ER-chaperones, all bearing the characteristic C-terminal tetrapeptide motif HDEL [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

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KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities

et al. 2022

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KDEL receptors (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. In doing this, KDELR participates in the ER quality control of newly synthesized proteins and the unfolded protein response. The binding of KDEL proteins to KDELR initiates 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. Considering the basic cellular functions performed by KDELRs, their association with various diseases is not surprising. KDELR mutants unable to bind the collagen-specific chaperon heat-shock protein 47 (HSP47) cause the osteogenesis imperfecta. Moreover, the overexpression of KDELRs appears to be linked to neurodegenerative diseases that share pathological ER-stress and activation of the unfolded protein response (UPR). Even immune function requires a functional KDELR1, as its mutants reduce the number of T lymphocytes and impair antiviral immunity. Several studies have also brought to light the exploitation of the shuttle activity of KDELR during the intoxication and maturation/exit of viral particles. Based on the above, KDELRs can be considered potential targets for the development of novel therapeutic strategies for a variety of diseases involving proteostasis disruption, cancer progression, and infectious disease. However, no drugs targeting KDELR functions are available to date; rather, KDELR has been leveraged to deliver drugs efficiently into cells or improve antigen presentation.

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Bioengineered Pancreas–Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia

et al. 2022

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Aberrant glucose homeostasis is the most common metabolic disturbance affecting one in ten adults worldwide. Prediabetic hyperglycemia due to dysfunctional interactions between different human tissues, including pancreas and liver, constitutes the largest risk factor for the development of type 2 diabetes. However, this early stage of metabolic disease has received relatively little attention. Microphysiological tissue models that emulate tissue crosstalk offer emerging opportunities to study metabolic interactions. Here, a novel modular multitissue organ-on-a-chip device is presented that allows for integrated and reciprocal communication between different 3D primary human tissue cultures. Precisely controlled heterologous perfusion of each tissue chamber is achieved through a microfluidic single "synthetic heart" pneumatic actuation unit connected to multiple tissue chambers via specific configuration of microchannel resistances. On-chip coculture experiments of organotypic primary human liver spheroids and intact primary human islets demonstrate insulin secretion and hepatic insulin response dynamics at physiological timescales upon glucose challenge. Integration of transcriptomic analyses with promoter motif activity data of 503 transcription factors reveals tissue-specific interacting molecular networks that underlie 𝜷-cell stress in prediabetic hyperglycemia. Interestingly, liver and islet cultures show surprising counter-regulation of transcriptional programs, emphasizing the power of microphysiological coculture to elucidate the systems biology of metabolic crosstalk.

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The Function of KDEL Receptors as UPR Genes in Disease

Cited by 14 publications

References 98 publications

PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue

PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue

KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities

Bioengineered Pancreas–Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia

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