The p97-UFD1L-NPL4 Protein Complex Mediates Cytokine-Induced IκBα Proteolysis

Abstract

IB␣ is an inhibitor of NF-B, a family of transcription factors that transactivate genes related to inflammation. Upon inflammatory stimuli, IB␣ is rapidly degraded via the ubiquitin-proteasome pathway. While it is very clear that the SCF ␤-TRCP ubiquitin ligase ubiquitinates IB␣ upon stimulation, little is known about the postubiquitinational events of IB␣ proteolysis. Here, we report that p97, a valosin-containing protein (also called VCP), plays an essential role in the postubiquitinational regulation of IB␣ turnover after tumor necrosis factor alpha (TNF-␣) or interleukin-1␤ (IL-1␤) treatment. The ATPase activity of p97 is essential for its role in IB␣ proteolysis. Moreover, we found that UFD1L and NPL4, two cofactors of p97, assist p97 to control the postubiquitinational regulation of IB␣. The p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated IB␣ via the interactions between p97 and the SCF ␤-TRCP ubiquitin ligase and between the polyubiquitin binding domain of UFD1L and polyubiquitinated IB␣. Furthermore, we observed that the postubiquitinational regulation of IB␣ by the p97-UFD1L-NPL4 complex is important for NF-B activation under stimuli.

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

“…VCP/p97 functions to unfold and extract proteins from macromolecular complexes in a ubiquitin-and ATP-dependent manner (18). For instance, VCP/p97 dissociates ubiquitylated IB␣ from NF-B, activating this transcription factor (77). VCP/p97 contributes to ER-associated degradation by extruding misfolded proteins from the secretory pathway for subsequent delivery to the proteasome (78).…”

The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis

“…Besides its quality control function, VCP/ p97 also governs crucial signaling pathways Yamanaka et al, 2012). Important examples are the degradation of IkBa (also known as NFKBIA), which leads to NFkB activation (Li et al, 2014), or degradation of HIF1a, which downregulates the hypoxic response (Alexandru et al, 2008). In other cases, the function of VCP/p97 is non-degradative; for instance, the extraction of transcription factor precursors from membranes for their subsequent activation, such as has been reported for Spt23, which regulates the expression of the fatty acid desaturase Ole1 in yeast, or Nrf1, which is involved in the homeostatic response (Jentsch and Rumpf, 2007;Radhakrishnan et al, 2014).…”

The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-κB Signaling via Partial Degradation of the NF-κB Subunit p100

“…For example, the p97-Npl4-Ufd1 complex regulates the turnover of HIF1␣, Cdt1, and CD4 (18,23). Recently, p97 was also shown to regulate IB␣ degradation by promoting SCF ␤TrCP ubiquitin ligasemediated K48 polyubiquitination, leading to the activation of canonical NF-B signaling pathway (24). However, it remains unknown whether p97 is involved in the regulation of the alternative NF-B signaling pathway.…”