Ubiquitin-associated Domain-containing Ubiquitin Regulatory X (UBX) Protein UBXN1 Is a Negative Regulator of Nuclear Factor κB (NF-κB) Signaling

Abstract

Background:Excessive NF-B hyperactivation should be tightly controlled in cells. Results: UBXN1 inhibits TNF␣-triggered NF-B signaling by sequestering cIAPs from being recruited to TNFR1. Conclusion: UBXN1 is a novel negative regulator of TNF␣-triggered NF-B signaling. Significance: Our study identified a novel ubiquitin-linked protein UBXN1 as a negative regulator of NF-B signaling pathway independent of VCP/p97 and provided important insight into the new regulatory mechanism of the UBX protein family.

UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer

“…The negative regulatory functions of FAF1 and p47 in the NF-κB pathway were previously covered in an earlier part of this review [93,108]. However, the overexpression experiments showed that UBXN1 has the strongest inhibiting ability on TNFα-triggered NF-κB activity in comparison to p47 and FAF1 [123]. Further experiments in cancer as well as immortalized noncancerous cell lines showed that knockdown of UBXN1 potentiates TNFα-triggered NF-κB signaling, suggesting UBXN1 is a physiological suppressor of the NF-κB pathway [123].…”

“…A siRNA screen of UBA domain-containing proteins revealed that silencing three members of the UBXD family, UBXN1, p47, and FAF1, can markedly potentiate TNFα-triggered NF-κB activation [123]. The negative regulatory functions of FAF1 and p47 in the NF-κB pathway were previously covered in an earlier part of this review [93,108].…”

“…However, the overexpression experiments showed that UBXN1 has the strongest inhibiting ability on TNFα-triggered NF-κB activity in comparison to p47 and FAF1 [123]. Further experiments in cancer as well as immortalized noncancerous cell lines showed that knockdown of UBXN1 potentiates TNFα-triggered NF-κB signaling, suggesting UBXN1 is a physiological suppressor of the NF-κB pathway [123]. Overexpression of wild-type and truncated forms of UBXN1 showed that 1) UBXN1 acts as a negative regulator upstream of the TAK1 and IKK complex in the NF-κB signaling pathway, and 2) the presence of the UBA domain is necessary for UBXN1-mediated NF-κB inhibition [123].…”

“…Binding cIAP1 and cIAP2 to the TNFR-associated death domain (TRADD)/TNFR-associated factor 2 (TRAF2) protein complex leads to Lys-63 ubiquitination of RIP1, which is necessary for downstream TAK1 and IKK complex recruitment [126]. A set of gain- and loss-of-function approaches confirmed that UBXN1 binds to cIAP1 protein and sequesters cIAP1 from recruiting to the TNFR1 signaling complex [123]. Reduction of cIAP-interacting TRAF2 decreases the ubiquitinated form of RIP1 within the TRAF2 complex, resulting in the inhibition of NF-κB signaling activity stimulated by TNFα.…”

“…UBXN-1 sequestration of cIAP1 is specific, since p47 and FAF1 failed to impair cIAP1 recruitment to TNFR1 in response to TNFα. Interestingly, the absence of p97 had no effect on UBXN1-mediated NF-κB inhibition (Figure 3) [123]. …”