Valosin-containing protein-Nuclear protein localization protein 4-Ubiquitin fusion degradation protein 1 complex (VCP-NPL4-UFD1)

The Valosin-containing protein-Nuclear protein localization protein 4-Ubiquitin fusion degradation protein 1 (VCP-NPL4-UFD1) complex is a critical molecular machine that functions as a segregase within the ubiquitin-proteasome pathway [1, 5]. It utilizes the energy from ATP hydrolysis, provided by the VCP (p97) AAA+ ATPase subunits, to extract polyubiquitinated proteins from membranes, such as the endoplasmic reticulum during ER-associated degradation (ERAD), or from large protein complexes [1, 4]. Once extracted and partially unfolded, these substrates are shuttled to the 26S proteasome for final degradation [5]. This complex is essential for maintaining cellular proteostasis and managing DNA damage, making it a high-priority target in oncology where cancer cells often exhibit a heightened dependency on protein quality control [3]. Therapeutic strategies include direct inhibition of VCP's ATPase activity or the disruption of the NPL4-UFD1 cofactor interaction, both of which lead to the accumulation of misfolded proteins and the induction of terminal endoplasmic reticulum stress and apoptosis [2, 3]. Clinical development of inhibitors like CB-5339 has focused on hematological and solid tumors, though challenges such as ocular toxicity have been observed with earlier generation compounds like CB-5083 [3, 4]. Citations: [1] Meyer, H., et al. (2012) J Cell Sci; [2] Skrott, Z., et al. (2017) Nature; [3] Anderson, D. J., et al. (2015) Cancer Cell; [4] Huryn, D. M., et al. (2020) Chem Rev; [5] Tang, W. K., & Xia, D. (2016) Front Mol Biosci.

Other names

p97-NPL4-UFD1 complexCDC48 complexVCP segregase complexp97 segregaseVCP-UFD1L-NPLOC4 complex

Inhibition of the AAA+ ATPase activity of VCP or disruption of the NPL4-UFD1 cofactor complex to prevent the extraction and delivery of ubiquitinated substrates to the 26S proteasome [1, 2, 3].