Calreticulin mutations affect its chaperone function and perturb the glycoproteome

Schürch, Patrick M.; Malinovska, Liliana; Hleihil, Mohammad; Losa, Marco; Hofstetter, Mara Carina; Wildschut, Mattheus H.E.; Lysenko, Veronika; Lakkaraju, Asvin K. K.; Maat, Christina A.; Benke, Dietmar; Aguzzi, Adriano; Wollscheid, Bernd; Picotti, Paola; Theocharides, Alexandre

doi:10.1016/j.celrep.2022.111689

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…Hence the presence of ASC specks, but not of BSA, accelerates SAA fibril formation. To confirm direct interaction and to map the protein domains of interaction between ASC and SAA, we employed the limited proteolysis-coupled mass spectrometry (LiP-MS) technology [31][32][33][34][35][36] which detects changes in peptide cleavage exerted by limited proteinase K (PK)-based proteolysis by mass spectroscopy (MS) 37 . If an interaction between proteins exists, certain epitopes become inaccessible to PK and the peptides detected by MS will display an altered profile (Fig.…”

Section: Asc Specks Interact With Saa Through the Pyrin Domain To Pro...mentioning

confidence: 99%

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The ASC inflammasome adapter controls the extent of peripheral protein aggregate deposition in inflammation-associated amyloidosis

Losa

Emmenegger

Rossi³

et al. 2021

Preprint

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The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) protein is a component of inflammasomes, inflammation-mediating complexes that include Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 3 (NLRP3). ASC and NLRP3 components aggregate to form ASC specks, which can cross-seed Aβ aggregation in Alzheimer’s disease (AD). Here we asked whether ASC is involved in additional protein misfolding diseases (PMDs). AA amyloidosis is a severe complication of chronic inflammatory conditions caused by the aggregation of Serum Amyloid A (SAA) protein. Since AA and Aβ aggregates share similar biochemical properties, such as β-sheet structures, we hypothesized that ASC inflammasomes may be involved in SAA/AA recruitment, aggregation, processing and removal. We therefore investigated the role of ASC in AA amyloidosis in vivo, employing a murine AA amyloidosis model in Asc-ablated mice. We show that ASC exerts a crucial role in SAA recruitment in the presence of AA fibrils, that splenic AA amyloid load was decreased in Asc-/- mice, that the presence of ASC accelerates SAA fibril formation and that ASC is important for SAA-activated phagocytosis of macrophages. We conclude that ASC modulates both SAA serum levels and the severity of AA amyloidosis in mice. ASC may represent a therapeutic target in AA as well as other amyloidosis entities.

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Section: Asc Specks Interact With Saa Through the Pyrin Domain To Pro...mentioning

confidence: 99%

“…LiP-MS was conducted as shown earlier [31][32][33][34][35] . Briefly, we incubated purified recombinants ASC protein or ExpiHEK cell native lysates containing ASC specks with human recombinant SAA1 proteins for 15 min at 37 °C in LiP buffer (100 mM HEPES pH 7.4, 150 mM KCl, 1mM MgCl2).…”

Section: Limited Proteolysis-coupled Mass Spectrometry (Lip-ms)mentioning

confidence: 99%

The ASC inflammasome adapter controls the extent of peripheral protein aggregate deposition in inflammation-associated amyloidosis

Losa

Emmenegger

Rossi³

et al. 2021

Preprint

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“…Calreticulin (CALR) is a kind of CaBP that is commonly found in the eukaryotic ER and is able to bind Ca 2+ in the ER (Baksh and Michalak, 1991;Michalak et al, 2009b). In addition to regulating Ca 2+ homeostasis, CALR is involved in a variety of cellular functions, including involvement in glycoprotein folding, Ca 2+ signaling, and cell adhesion (Schurch et al, 2020).…”

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confidence: 99%

Calreticulin (CALR) Promotes Ionophore-Induced Microneme Secretion in Toxoplasma gondii

Shan,

Song,

Yang

et al. 2023

Preprint

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The flow of calcium ions (Ca2+) is involved in numerous vital activities of Toxoplasma gondii. Calreticulin is a type of Ca2+-binding protein in the endoplasmic reticulum (ER), that is involved in Ca2+ signaling pathway regulation, Ca2+ storage, and protein folding. In this work, the calreticulin (CALR), a protein predicted to possess a conserved domain of calreticulin in T. gondii, was characterized. The CALR localized in the ER. Using reverse genetics, we discovered that CALR is not necessary for the lytic cycle, including invasion and replication. However, depletion of CALR affected microneme secretion triggered by A23187, which is a Ca2+ ionophore used to increase cytoplasmic Ca2+ concentration. Furthermore, we discovered that CALR influences Ca2+ release. Transcriptomic comparison between Δcalr and Δku80 parasites showed that 226 genes in the Δcalr parasites were significantly down-regulated (p<0.05). The cellular biological functions of the down-regulated genes were mainly involved in calmodulin-dependent protein kinase pathways. Furthermore, in the absence of CALR, tachyzoites were still able to cause acute infection in mice. These results imply that by influencing ER Ca2+ release content, CALR may further impair the ionophore-induced secretion of the parasite. However, this protein is not required for the completion of the parasite's lytic cycle or for the acute virulence of the parasite.

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Calreticulin (CALR) promotes ionophore-induced microneme secretion in Toxoplasma gondii

Shan,

Song,

Yang

et al. 2024

Parasitol Res

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Calreticulin mutations affect its chaperone function and perturb the glycoproteome

Cited by 3 publications

References 53 publications

The ASC inflammasome adapter controls the extent of peripheral protein aggregate deposition in inflammation-associated amyloidosis

The ASC inflammasome adapter controls the extent of peripheral protein aggregate deposition in inflammation-associated amyloidosis

Calreticulin (CALR) Promotes Ionophore-Induced Microneme Secretion in Toxoplasma gondii

Calreticulin (CALR) promotes ionophore-induced microneme secretion in Toxoplasma gondii

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