A Proliferation-Inducing Ligand (APRIL)—also known as TNFSF13 (Tumor Necrosis Factor Superfamily Member 13) —is a secreted protein that belongs to the tumor necrosis factor (TNF) ligand superfamily.
A proliferation-inducing ligand is a TNF-superfamily cytokine that drives B-cell and plasma-cell survival and proliferation by binding the receptors TACI and BCMA.
Encoded by the TNFSF13 gene, APRIL is synthesized as a type II transmembrane precursor that is typically processed and cleaved in the Golgi apparatus by the protease furin to act solely as a soluble factor.
APRIL shares receptors with a related TNF family member, BAFF (B-cell activating factor).
APRIL binds primarily to: BCMA (B-cell maturation antigen / TNFRSF17) TACI (Transmembrane activator and calcium modulator and cyclophilin ligand interactor / TNFRSF13B)
Unlike BAFF, APRIL does not bind to the BAFF-R receptor.
It can also interact with certain heparan sulfate proteoglycans.
APRIL plays a major role in the survival, maturation, and activation of B cells, the long-term survival of plasma cells in the bone marrow, and immunoglobulin class-switching (especially IgA).
Elevated levels of APRIL have been implicated in autoimmune conditions and notably in the pathogenesis of IgA nephropathy (IgAN), making APRIL a key therapeutic target in clinical trials.
Cancers: APRIL is overexpressed in various hematological malignancies (such as multiple myeloma and chronic lymphocytic leukemia) and solid tumors, where it can promote tumor cell growth and survival.
Source: made mostly by myeloid cells (monocytes, macrophages, dendritic cells, neutrophils) and by bone marrow and gut stromal cells.
APRIL is cleaved by furin and released in soluble form. It also binds heparan sulfate proteoglycans.
Related to BAFF (BLyS): BAFF shares TACI and BCMA with APRIL. BAFF-R binds BAFF only.
It supports long-lived plasma cells in the bone marrow, IgA class switching (T-cell-independent), and antibody responses.
Signaling: in follicular lymphoma B cells, binding to TACI turns on the PI3K–Akt–mTOR pathway (p70S6K, 4E-BP1), phosphorylates Rb, and raises cyclin D1.
This drives proliferation. NF-κB activation is also well described.
APRIL is present in the tumor microenvironment of follicular lymphoma.
It also supports multiple myeloma and CLL cells, which is part of why BCMA is a target in myeloma (CAR-T cells, bispecific antibodies, antibody–drug conjugates).
IgA nephropathy: APRIL drives production of galactose-deficient IgA1, which is central to the disease.
Anti-APRIL antibodies (sibeprenlimab, zigakibart) and dual BAFF/APRIL blockers (atacicept, telitacicept, povetacicept) are late-stage development or newly approved for IgA nephropathy.
Autoimmunity: dual BAFF/APRIL blockade is being studied in SLE, Sjögren disease, and myasthenia gravis.
Belimumab, by contrast, blocks BAFF only.