Dataset Information

Mass spectrometry-based determination of R. prolixus hemoglobinases cleavage preferences

ABSTRACT: Characterization of the clevage sites of Rhodnius prolixus midgut-associated hemoglobinase.s

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Homo Sapiens (human) Rhodnius Prolixus (triatomid Bug)

TISSUE(S): Blood

DISEASE(S): Chagas Disease

SUBMITTER: Radouane OUALI

LAB HEAD: Radouane OUALI

PROVIDER: PXD044620 | Pride | 2024-04-28

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Search.sf3	Other
	Subset-Database.fasta	Fasta
	ULB-230130-SB-RO-HB-in-vitro-digestion.mzid.gz	Mzid
	ULB-230130-SB-RO-HB-in-vitro-digestion.mzid.gz_ULB-SB-OR-230123-A1_Slot1-3_1_7129_5.3.556_F070967.MGF	Mzid
	ULB-230130-SB-RO-HB-in-vitro-digestion.mzid.gz_ULB-SB-OR-230123-A2_Slot1-7_1_7130_5.3.556_F070970.MGF	Mzid

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Project description:Polycystic liver disease (PLD) is a group of genetic disorders characterized by bile duct dilatation and/or progressive development of multiple intrahepatic fluid-filled biliary cysts (>10), which are the main cause of morbidity. Current surgical and/or pharmacological therapies exert short-term and modest benefits, and thus liver transplantation represents the only curative option. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. Here, we hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. In this regard, ER stress was assessed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy; TEM) and functional (20S proteasome activity) levels in different models of PLD (i.e., human and rat). Moreover, PCK rat (animal model of PLD) was employed to determine the effects of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or inducers [tunicamycin (TM)] in hepatic cytogenesis and, consequently, in the progression of the disease. Likewise, the impact of the aforementioned ER stress modulators was also analyzed on the expression of unfolded protein response (UPR) factors, the 20S proteasome activity, the mechanisms involved in the maintenance of ER proteostasis and the cell fate decisions (i.e., survival/apoptosis). Interestingly, the expression levels of the UPR factors were markedly upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Additionally, cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (i.e., synthesis, folding, trafficking and degradation of nascent proteins), marked enlargement of the ER lumen (by TEM), and hyperactivation of the 20S proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline or TM administration compared to control groups. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized, at least in part, proteomic profiles related to protein synthesis, folding, trafficking and degradation, and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusion: Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel and promising therapeutic strategy.

Dataset Information

Mass spectrometry-based determination of R. prolixus hemoglobinases cleavage preferences

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