Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase

Abstract

Tumor necrosis factor (TNF) ligand family members are synthesized as transmembrane proteins, and cleavage of the membrane-anchored proteins from the cell surface is frequently observed. The TNF-related ligands APRIL and BLyS and their cognate receptors BCMA/TACI form a two ligand/two receptor system that has been shown to participate in B-and T-cell stimulation. In contrast to BLyS, which is known to be cleaved from the cell surface, we found that APRIL is processed intracellularly by furin convertase. Blockage of protein transport from the endoplasmic reticulum to the Golgi apparatus by Brefeldin A treatment abrogated APRIL processing, whereas monensin, an inhibitor of post-Golgi transport, did not interfere with cleavage of APRIL, but blocked secretion of processed APRIL. Thus, APRIL shows a unique maturation pathway among the TNF ligand family members, as it not detectable as a membrane-anchored protein at the cell surface, but is processed in the Golgi apparatus prior to its secretion.

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…Secondly, there exists a specific consensus furin-like sequence in the chromosomal organization of both APRIL and BAFF genes, which enables the release of mature forms of APRIL and BAFF [32,34]. Furthermore, the in vitro studies showed that furin can directly cleave unprocessed APRIL into the mature form and this effect can be abrogated by the furin inhibitor, chloromethylketone [35]. APRIL and BAFF play important roles in the development of atherosclerotic lesions and plaque stabilization [36e38].…”

Abnormal production of the TNF-homologue APRIL increases the proliferation of human malignant glioblastoma cell lines via a specific receptor

“…The presence of APRIL mRNA suggests that APRIL was secreted because the APRIL protein exists only as a soluble form (Lo´pez-Fraga et al, 2001). The low affinity of the available commercial antibodies precluded adequate quantification of the exact amounts of APRIL in culture supernatants.…”

“…APRIL is produced in small amounts in peripheral blood lymphocytes (PBLs) and normal tissue but is produced in much larger quantities in malignant tumours, in which it stimulates the growth of malignant cells (Hahne et al, 1998). APRIL, which is processed by furin convertase within the cell before its secretion, is detected only in soluble form (Lo´pez-Fraga et al, 2001). Roth et al (2001) reported APRIL to be present in some malignant glioblastoma cell lines, but with no stimulatory effect on cell growth.…”

Knockdown of a Proliferation-inducing Ligand (PRIL) Suppresses the Proliferation of Gastric Cancer Cells

“…It was originally identified in cell lines and primary samples from various tumor lesions in 1998 and named for its capacity to stimulate the proliferation of tumor cells (Hahne et al, 1998). In contrast to most TNF family members, APRIL is processed in the Golgi apparatus into the active soluble form by a furin convertase (Lopez-Fraga et al, 2001). APRIL is expressed by a subset of immune cells that also produce B-cell activating factor (BAFF): monocytes, macrophages, (Hahne et al, 1998;Nardelli et al, 2001;He et al, 2004;Chu et al, 2007) as well as in some non-immune cells such as epithelial cells and osteoclasts.…”