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Proapelin is processed extracellularly in a cell line-dependent manner with clear modulation by proprotein convertases.

ABSTRACT: Apelin is a peptide hormone that binds to a class A GPCR (the apelin receptor/APJ) to regulate various bodily systems. Upon signal peptide removal, the resulting 55-residue isoform, proapelin/apelin-55, can be further processed to 36-, 17-, or 13-residue isoforms with length-dependent pharmacological properties. Processing was initially proposed to occur intracellularly. However, detection of apelin-55 in extracellular fluids indicates that extracellular processing may also occur. To test for this, apelin-55 was applied exogenously to HEK293A cells overexpressing proprotein convertase subtilisin kexin 3 (PCSK3), the only apelin processing enzyme identified thus far, and to differentiated 3T3-L1 adipocytes, which endogenously express apelin, PCSK3 and other proprotein convertases. Analysis of culture media constituents from each cell type by high performance liquid chromatography-mass spectrometry and western blot demonstrated a time-dependent decrease in apelin-55 levels. This decrease was partially, but not fully, attenuated by PCSK inhibitor treatment in both cell lines. Comparison of the resulting apelin-55-derived peptide profile between the two cell lines demonstrated distinct processing patterns, with apelin-36 production apparent in 3T3-L1 adipocytes vs. detection of the prodomain of a shorter isoform (likely the apelin-13 prodomain, observed after additional proteolytic processing) in PCSK3-transfected HEK293A cells. Extracellular processing of apelin, with distinct cell type dependence, provides an alternative mechanism to regulate isoform-mediated physiological effects of apelin.

SUBMITTER: Shin K

PROVIDER: S-EPMC7101949 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Proapelin is processed extracellularly in a cell line-dependent manner with clear modulation by proprotein convertases.

Shin Kyungsoo K Landsman Michael M Pelletier Stephanie S Alamri Bader N BN Anini Younes Y Rainey Jan K JK

Amino acids 20181115 3

Apelin is a peptide hormone that binds to a class A GPCR (the apelin receptor/APJ) to regulate various bodily systems. Upon signal peptide removal, the resulting 55-residue isoform, proapelin/apelin-55, can be further processed to 36-, 17-, or 13-residue isoforms with length-dependent pharmacological properties. Processing was initially proposed to occur intracellularly. However, detection of apelin-55 in extracellular fluids indicates that extracellular processing may also occur. To test for th ...[more]

PMID: 30430332

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Project description:Proprotein convertases (PCs), also known as eukaryotic subtilases, are a group of serine proteases comprising furin (PACE), PC1 (PC3), PC2, PC4, PACE4, PC5 (PC6), and PC7 (LPC, PC8) that generate bioactive proteins and peptides, such as hormones, receptors, and growth factors by cleaving precursor proteins at multibasic motifs. Two other family members, SKI-1/S1P and PCSK9, cleave regulator proteins involved in cholesterol and fatty acid homeostasis at nonbasic peptide bonds. Furin is ubiquitous in eukaryotic tissues and cells. PACE4, PC5, and PC7 are also widespread, whereas the expression of the other PCs is more restricted. PCs are synthesized as multi-segmented zymogens which are autocatalytically activated. The prodomains have regulatory and inhibitory functions. The catalytic domains are the most conserved domains among the PCs. The architecture of the catalytic active furin domain is known in different binding states. The C-terminal parts of the PCs differ in length and structure and contain encoded peptide signatures guiding the PCs to the subcellular destinations on the secretory pathways: SKI-1/S1P to the cis-Golgi, furin, PC5B, and PC7 to the TGN region but also to the plasma membrane. PACE4, PC5A, and PCSK9 are attached at the cell surface. Truncated, soluble furin and SKI-1/S1P, as well as PC1 and PC2, are released into the extracellular matrix. Many enveloped viruses are activated by furin and furin-like PCs and arenaviruses and a few bunyaviruses by SKI-1/S1P. The PCs cleave the viral fusion glycoprotein to trigger fusion of viral envelopes with cellular membranes to deliver the viral genome into host cells. Cleavage by PCs, occasionally in concert with other endoproteases, enables conformational changes in the viral membrane proteins needed for correct oligomerization of glycoprotein spikes and their effective incorporation into virions. Mutational alterations of PC cleavage sites can reduce the fusion potential of viral surface proteins and thus facilitate the development of secure live attenuated vaccines. Alternatively, agents preventing cleavage of viral surface (glyco)proteins block fusion capacity and multicyclic virus replications. PC inhibitors are suggested as promising antiviral drugs for quite a number of viruses causing severe infections.

Dataset Information

Proapelin is processed extracellularly in a cell line-dependent manner with clear modulation by proprotein convertases.

Publications

Proapelin is processed extracellularly in a cell line-dependent manner with clear modulation by proprotein convertases.

Similar Datasets

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