KDEL Receptors Are Differentially Regulated to Maintain the ER Proteome under Calcium Deficiency

Trychta, Kathleen A.; Bäck, Susanne; Henderson, Mark J.; Harvey, Brandon K.

doi:10.1016/j.celrep.2018.10.055

Cited by 106 publications

(186 citation statements)

References 66 publications

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…However, some cellular and proteomic analyses have identified additional targetssuch as histones and cytosolic Hsp70 and Hsp40 family chaperones -that localize to cellular compartments other than the ER [30], [31], [40]. How HYPE interacts physiologically with these non-ER localized proteins is unclear [54], though a recent report reveals that a mass exodus of ER resident proteins occurs in response to ER Ca 2+ depletion [41]. Additionally in C. elegans, HYPE is reported to be partially present in the cytosol in addition to the ER lumen [29].…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

Sanyal¹,

Dutta

Chandran

et al. 2019

Preprint

View full text Add to dashboard Cite

During disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called UPR (Unfolded Protein Response) that functions to maintain ER (endoplasmic reticulum) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification (PTM) called Fic-mediated Adenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an AMP (adenosine monophosphate) to the ER chaperone, BiP, to alter the UPR-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE - alpha-Synuclein (aSyn), a presynaptic protein involved in Parkinsons disease (PD). Aggregated aSyn has been shown to induce ER stress and elicit neurotoxicity in PD models. We show that HYPE adenylylates aSyn and reduces phenotypes associated with aSyn aggregation in vitro, suggesting a possible mechanism by which cells cope with aSyn toxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

Sanyal¹,

Dutta

Chandran

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The KDEL receptor is a seven-transmembrane-domain protein whose function is to 294 sort and retrieve proteins bearing a KDEL sequence (calnexin, GRP78, PDI, for instance) and 295 possibly proteins with KDEL-like sequences (Erp72, MANF and CDNF) from the Golgi 296 complex to the ER/SR (Dorner et al, 1990;Voutilainen et al, 2015;Becker et al, 2016). The 297 importance of KDEL-R to cardiomyocyte homeostasis was demonstrated by studying 298 transgenic mice that express a mutant KDEL-R in which reverse transport from Golgi to 299 ER/SR was compromised.…”

Section: Kdel-r In the Membrane Binds Cdnf And Mediates Its Cardiopromentioning

confidence: 99%

“…Recent studies, however, have suggested that the KDEL-R has additional functions 301 and new cellular localizations, including the plasma membrane. In this regard, there is 302 mounting evidence for the presence of KDEL-R at the surface of mammalian cells, where the 303 receptor binds cargo proteins such as A/B microbial toxins K28, MANF and other proteins in 304 which a KDEL-sequence is present at the C-terminus (Riffer et al, 2002;Henderson et al, 305 2013;Becker et al, 2016;Trychta et al, 2018). Trychta and collaborators (2018) have coined 306 the term "ER exodosis" in an elegant study where they showed a massive departure of proteins 307 containing KDEL-related sequences upon calcium-induced ER-stress in several mammalian 308 cell lines.…”

Section: Kdel-r In the Membrane Binds Cdnf And Mediates Its Cardiopromentioning

confidence: 99%

“…Calcium-induced ER/SR-stress increases the secretion of MANF and CDNF 339 (and also other ER/SR-resident proteins), [Figure 1 and ( Bai et al, 2018)] to the extracellular 340 milieu. ER-stress also enhances the expression of KDEL-R through the action of the 341 transcription factor XBP1 (Trychta et al, 2018), increasing the presence of KDEL-R at the 342 cell membrane (Henderson et al, 2013). Outside the cells, MANF and CDNF would establish 343 an initial "unspecific" contact (mediated by sulfatide in the case of MANF) with the lipid 344 bilayer through its N-domain and a further specific interaction with newly arrived KDEL-R 345 through its C-terminal domain.…”

Section: Kdel-r In the Membrane Binds Cdnf And Mediates Its Cardiopromentioning

confidence: 99%

See 1 more Smart Citation

Cerebral dopamine neurotrophic factor (CDNF) reduces myocardial ischemia/reperfusion injuries by the activation of PI3K-AKT via KDEL-receptor binding

Maciel

Oliveira

Mesquita

et al. 2019

Preprint

View full text Add to dashboard Cite

30CDNF (Cerebral Dopamine Neurotrophic Factor) belongs to a new family of NF, which 31 presents several beneficial activities beyond the brain. Little is known about CDNF in the 32 cardiac context. Herein we investigate CDNF effects in cardiomyocytes under endoplasmic 33 reticulum (ER)-stress and in whole rat hearts subjected to ischemia/reperfusion (I/R). We 34 showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated 35 hearts subjected to I/R. CDNF protects human and mouse cardiomyocytes against ER-stress 36 by restoring the calcium transient, and isolated heart against I/R injuries by reducing the 37 infarct area and avoiding mitochondrial impairment. This protection is abrogated by 38 wortmannin (PI3K-inhibitor) or by heptapeptides containing KDEL sequence, which block 39 KDEL-receptor. These data suggest that CDNF induces cardioprotection via KDEL receptor 40 binding and PI3K/AKT activation. This is the first study to propose CDNF as a cardiomyokine 41 and to unravel the receptor and signaling pathway for this interesting family of NF. 42

show abstract

“…The KDEL-Receptors (KDELRs) are a family of seventransmembrane-domain ER protein retention receptors consisting of three members (KDELR1, 2 and 3) that function in the ER Stress Response (ERSR). They share structural homology, but each isoform can have different ligands 18,19 . They are responsible for the retrograde transport of protein machinery from the Golgi to the ER, including chaperones that target unfolded proteins for refolding, and whose disassociation from membrane receptors stimulates UPR signaling 19,20 .…”

mentioning

confidence: 99%

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Marie

Sassano

Yang

et al. 2019

Preprint

View full text Add to dashboard Cite

Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posited that melanoma cells acquire metastatic capability by adopting an embryonic-like phenotype, and that a lineage approach would uncover novel metastatic melanoma biology. We used a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, identified melanoblast-specific genes whose expression contributed to metastatic competence, and derived a 43-gene signature that predicted patient survival. We identified a melanoblast gene, KDELR3, whose loss impaired experimental metastasis. In contrast, KDELR1 deficiency enhanced metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover novel targetable pathways for melanoma therapy.Melanoma is an aggressive cancer that frequently progresses to metastatic proficiency. Treatment of metastatic melanoma remains a challenge, highlighting an urgent need to uncover new targets that could be used in the clinic to broaden therapeutic options. In the early 19 th century, Virchow first described cancer cells as being "embryonic-like" 1 . Developmental systems have since proven useful to study melanoma, and melanoma cell plasticity appears to be a key feature of melanoma progression. Melanocyte lineage pathways are a recurring theme in melanoma etiology, reinforcing the importance of uncovering new melanocyte developmental pathways and biology 2-13 . Here we use a genetically engineered mouse (GEM), designed to facilitate the isolation and analysis of developing melanocytes (melanoblasts), to attempt to uncover new targets relevant to melanoma metastasis.Melanocytes are neural crest-derived cells whose development necessitates extensive migration/invasion to populate the skin and other sites 14 . This process requires melanoblasts to adopt a migratory phenotype, to interact with and survive in foreign microenvironments and to colonize distant sites − functions that are analogous to metastatic competence 15 . To complete these processes, the cell may encounter numerous cellular stressors, such as shear stress, nutrient deprivation, hypoxia, lipid stress and oxidative stress 16 . The cellular impact of these stressors converges at the Endoplasmic Reticulum (ER), the organelle tied closely to protein synthesis and responsible for correct protein folding, protein quality control and post-translational modifications.Stress stimuli can result in aberrant ER function, a build-up of unfolded/misfolded proteins (ER stress), and an overwhelmed system. The ER can therefore be viewed as an exquisitely sensitive stress sensor. Upon ER stress insult, the ER launches an immediate counter measure known as of the Unfolded Protein Response (UPR) 17 . T...

show abstract

KDEL Receptors Are Differentially Regulated to Maintain the ER Proteome under Calcium Deficiency

Cited by 106 publications

References 66 publications

Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

Cerebral dopamine neurotrophic factor (CDNF) reduces myocardial ischemia/reperfusion injuries by the activation of PI3K-AKT via KDEL-receptor binding

Melanoblast transcriptome analysis reveals novel pathways promoting melanoma metastasis

Contact Info

Product

Resources

About