Endophilin A2 (SH3GL1)

Endophilin A2 (SH3GL1) is a cytoplasmic adaptor protein of the endophilin family, characterized by an N-terminal BAR domain and a C-terminal SH3 domain, which promotes membrane curvature and recruits other proteins to sites of dynamic endocytosis. It is essential for clathrin-mediated endocytosis, notably internalization and recycling of the T cell receptor, and regulates crucial cell biological processes such as ferroptosis and autophagy via modulation of ferritin heavy chain 1 (FTH1) and iron homeostasis pathways. Pathologically, it is upregulated in certain cancers such as diffuse large B-cell lymphoma, where it drives cell proliferation, inhibits ferroptosis-induced cell death, and is associated with chemotherapy resistance. In the immune system, SH3GL1 is required for proper T cell activation and function, and its genetic inactivation in preclinical models protects against autoimmune diseases via loss of autoreactive T cell effector function. SH3GL1 forms fusion genes in leukemias (e.g., EEN/MLL) and is an effective tumor antigen, capable of eliciting antibody responses in gliomas. Targeting SH3GL1 is being explored both for immunomodulation in autoimmunity and as a therapeutic vulnerability in hematological malignancies.

Other names

Endophilin-2SH3 domain-containing GRB2-like protein 1EENSH3P8CNSA1SH3D2BExtra eleven-nineteen leukemia fusion gene proteinEEN fusion partner of MLLSH3 domain protein 2BSH3-containing Grb-2-like 1 proteinSH3 domain GRB2-like 1MGC111371

Drugs targeting SH3GL1 could inhibit endocytosis or TCR internalization in T cells; Regulation of ferroptosis sensitivity and autophagy by modulating iron homeostasis (via FTH1)