An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein

Abstract

TWEAK and APRIL are two recently identified tumour necrosis factor (TNF) ligand family members, implicated in angiogenesis and immune regulation, respectively. TWEAK is a transmembrane protein expressed on the cell surface, whereas APRIL acts solely as a secreted factor. In this report, using RACE, RT-PCR, cDNA library screening and an RNase protection assay, we characterize a hybrid transcript between TWEAK and APRIL mRNAs. The encoded TWE-PRIL protein is composed of TWEAK cytoplasmic and transmembrane domains fused to the APRIL C-terminal domain. TWE-PRIL mRNA is expressed and translated in human primary T cells and monocytes, and endogenous TWE-PRIL protein was detected in primary human T lymphocytes and monocytic cell lines. TWE-PRIL is membrane anchored and presents the APRIL receptor-binding domain at the cell surface. It is a biologically active ligand, as it stimulates cycling in T- and B-lymphoma cell lines. Much like membrane-bound and secreted TNF-alpha, the different cellular localizations of TWE-PRIL and APRIL suggest that they exert distinct biological roles.

The role of APRIL and BAFF in lymphocyte activation

“…TWE-PRIL (TWEAK-APRIL fusion protein) is a fusion protein containing the TNF homology domain of APRIL fused to the aminoterminal portion of another TNF family ligand, TWEAK (TNF-related weak inducer of apoptosis). TWE-PRIL might represent a membrane-bound form of APRIL [11]. In addition, a splice variant of BAFF (DBAFF) inhibits regular BAFF by forming inactive heteromers [12].…”

Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK

“…APRIL is also an important regulator of T-cellindependent class-switch pathways in B cells. An intergene splicing transcript TWE-PRIL, which combines the first six exons of TWEAK and the last five exons of APRIL, was identified in activated T cells and monocytes (34). TWE-PRIL is a membraneanchored protein that possesses the intracellular transmembrane stalk region of TWEAK but the receptor-binding domain of APRIL, thus signaling through the APRIL binding domain may be linked to downstream pathways shared with the TWEAK intracellular domain.…”

The uncertain glory of APRIL

“…17,[21][22][23] In addition, endogenous APRIL protein has been detected in human myeloid leukaemia cell lines, including U937 and Mono Mac 1. 24 The effect APRIL exerts on tumours has been explained in two ways. First of all, a glioblastoma cell line was described to have been made resistant to death-induced apoptosis by transfection with APRIL; 23 this was associated with upregulation of X-linked inhibitor of apoptosis (XIAP), a member of the inhibitor of apoptosis (IAP) family that blocks death via inhibition of downstream caspase activity and/or activation.…”