Limited ER quality control for GPI-anchored proteins

Sikorska, Natalia; Lemus, Leticia; Aguilera-Romero, Auxiliadora; Manzano-López, Javier; Riezman, Howard; Muñiz, Manuel; Goder, Veit

doi:10.1083/jcb.201602010

Cited by 46 publications

(54 citation statements)

References 47 publications

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“…This behaviour is reminiscent of the fate of destabilized GPI‐APs in mammals and yeast that are not retained in the ER but are secreted and targeted to the lysosome for destruction. The molecular mechanism how abnormal GPI‐anchored proteins are preferentially directed to endosomes from the plasma membrane remains to be established (Satpute‐Krishnan et al ., ; Sikorska et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Arabidopsis thaliana FLA4 functions as a glycan‐stabilized soluble factor via its carboxy‐proximal Fasciclin 1 domain

et al. 2017

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SummaryFasciclin‐like arabinogalactan proteins (FLAs) are involved in numerous important functions in plants but the relevance of their complex structure to physiological function and cellular fate is unresolved. Using a fully functional fluorescent version of Arabidopsis thaliana FLA4 we show that this protein is localized at the plasma membrane as well as in endosomes and soluble in the apoplast. FLA4 is likely to be GPI‐anchored, is highly N‐glycosylated and carries two O‐glycan epitopes previously associated with arabinogalactan proteins. The activity of FLA4 was resistant against deletion of the amino‐proximal fasciclin 1 domain and was unaffected by removal of the GPI‐modification signal, a highly conserved N‐glycan or the deletion of predicted O‐glycosylation sites. Nonetheless these structural changes dramatically decreased endoplasmic reticulum (ER)‐exit and plasma membrane localization of FLA4, with N‐glycosylation acting at the level of ER‐exit and O‐glycosylation influencing post‐secretory fate. We show that FLA4 acts predominantly by molecular interactions involving its carboxy‐proximal fasciclin 1 domain and that its amino‐proximal fasciclin 1 domain is required for stabilization of plasma membrane localization. FLA4 functions as a soluble glycoprotein via its carboxy‐proximal Fas1 domain and its normal cellular trafficking depends on N‐ and O‐glycosylation.

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Section: Discussionmentioning

confidence: 97%

Arabidopsis thaliana FLA4 functions as a glycan‐stabilized soluble factor via its carboxy‐proximal Fasciclin 1 domain

et al. 2017

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“…Such a process would seem to be the most efficient mechanism for disposal of misfolded VSG. However, in yeast and mammalian cells misfolded GPI‐anchored proteins are actually exported to the lysosome for degradation . This is because the GPI anchor is a forward trafficking signal for ER exit.…”

Section: When Good Vsg Goes Bad: Coping With Failed Antigenic Variationmentioning

confidence: 99%

“…However, in yeast and mammalian cells misfolded GPI-anchored proteins are actually exported to the lysosome for degradation. [46,47] This is because the GPI anchor is a forward trafficking signal for ER exit. This sets up a dynamic tension between retention by ER quality control versus packaging into secretory cargo transport vesicles À in these model organisms ER exit is the winner.…”

Section: Just Right: How Do Trypanosomes Precisely Regulate Vsg Synthmentioning

confidence: 99%

Evolution of Antigenic Variation in African Trypanosomes: Variant Surface Glycoprotein Expression, Structure, and Function

Bangs

2018

BioEssays

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The process of antigenic variation in parasitic African trypanosomes is a remarkable mechanism for outwitting the immune system of the mammalian host, but it requires a delicate balancing act for the monoallelic expression, folding and transport of a single variant surface glycoprotein (VSG). Only one of hundreds of VSG genes is expressed at time, and this from just one of ~15 dedicated expression sites. By switching expression of VSGs the parasite presents a continuously shifting antigenic facade leading to prolonged chronic infections lasting months to years. We have known the basics of VSG structure and switching for several decades, but recent studies have brought higher resolution to many aspects this process. New VSG structures, in silico modeling of infections, studies of VSG codon usage, and experimental ablation of VSG expression provide insights that inform how this remarkable system may have evolved.

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“…These observations together with the recent RESET pathway description, led to the postulation that the presence of a GPI anchor might obstruct ERAD for sterical hindrance [20]. However, findings from Sikorska and colleagues [23] demonstrated that the misfolded GPI-anchored protein Gas1* in yeast, is targeted to HRD1-dependent ERAD pathway, ruling out that a GPI anchor obstructs ERAD. Instead, the normally decreased ERAD for Gas1* is caused by remodelling of its GPI anchor (which occurs in all GPI-APs), thus proposing the new concept that the canonical remodelling of GPI anchor universally limits the ER quality control of GPI-APs.…”

Section: Quality Control Of Prpmentioning

confidence: 99%

Untangling the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

Sarnataro¹

2018

Preprint

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The misfolding and aggregation of proteins is the neuropathological hallmark of numerous diseases including Alzheimer's disease, Parkinson's disease, and prion diseases. It is believed that misfolded and abnormal -sheets forms of wild-type proteins are the vectors of these diseases by acting as seeds for the aggregation of endogenous proteins. Cellular prion protein (PrP C ) is a glycosyl-phosphatidyl-inositol (GPI) anchored glycoprotein which is able to misfold to a pathogenic isoform PrP Sc , the causative agent of prion diseases which present as sporadic, dominantly inherited and transmissible infectious disorders. Increasing evidence highlight the importance of prion-like seeding as a mechanism for pathological spread in Alzheimer's disease and tauophaty, as well as other neurodegenerative disorders.Here, we report the latest findings on the mechanisms controlling protein folding, focusing on the ER quality control of GPI-anchored proteins and describe the "prion-like" properties of amyloid- and tau assemblies. Furthermore, we highlight the importance of pathogenic assemblies interactions with protein and lipid membrane components and their implications in both prion and Alzheimer's diseases.

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Limited ER quality control for GPI-anchored proteins

Cited by 46 publications

References 47 publications

Arabidopsis thaliana FLA4 functions as a glycan‐stabilized soluble factor via its carboxy‐proximal Fasciclin 1 domain

Arabidopsis thaliana FLA4 functions as a glycan‐stabilized soluble factor via its carboxy‐proximal Fasciclin 1 domain

Evolution of Antigenic Variation in African Trypanosomes: Variant Surface Glycoprotein Expression, Structure, and Function

Untangling the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

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