RLIP76

RLIP76, also known as RALBP1 (Ral-binding protein 1), is a 76-kilodalton cytosolic protein that functions as a multifunctional regulator in humans and other organisms. It acts as an effector of the small GTPases RalA and RalB, binding selectively to the GTP-bound forms and participating in membrane trafficking and endocytosis. In addition to its role in Ral signaling, RLIP76 contains a RhoGAP-like domain that can stimulate GTP hydrolysis of Rac1 and Cdc42 in vitro, linking it to actin cytoskeleton remodeling and cell motility.

RLIP76 also serves as an ATP-dependent transporter of glutathione-conjugates and various hydrophobic xenobiotics. It exports glutathione-conjugated electrophiles (GS-E) from cells, contributing to cellular detoxification and oxidative stress defense. This transporter activity affects cellular sensitivity to chemotherapy and is a notable factor in multidrug resistance in cancer cells.

Structurally, RLIP76 is approximately 655 amino acids in length and localizes to the cytosol while associating with membranes and endocytic machinery via interactions with adaptor proteins such as AP2 and clathrin. The N-terminal region mediates Ral binding, while the central region harbors the RhoGAP-like domain; the C-terminal region contributes to protein–protein interactions.

RLIP76 is broadly expressed in tissues; its activity links signaling and detoxification. In cancer, RLIP76 expression and activity have been associated with tumor cell survival and drug resistance; preclinical studies have explored RLIP76 inhibition or depletion as a strategy to sensitize tumors to chemotherapy and to reduce metastatic potential. Research continues to define its precise contributions to endocytosis, cytoskeletal control, and detoxification pathways.