Proteasomal Degradation Is Transcriptionally Controlled by TCF11 via an ERAD-Dependent Feedback Loop

Abstract

Coordinated regulation of the ubiquitin-proteasome system (UPS) is crucial for the cell to adjust its protein degradation capacity to changing proteolytic requirements. We have shown previously that mammalian cells upregulate proteasome gene expression in response to proteasome inhibition. Here, we report the identification of the transcription factor TCF11 (long isoform of Nrf1) as a key regulator for 26S proteasome formation in human cells to compensate for reduced proteolytic activity. Under noninducing conditions, TCF11 resides in the endoplasmic reticulum (ER) membrane. There, TCF11 is targeted to ER-associated protein degradation requiring the E3 ubiquitin ligase HRD1 and the AAA ATPase p97. Proteasome inhibitors trigger the accumulation of oxidant-damaged proteins and promote the nuclear translocation of TCF11 from the ER, permitting activation of proteasome gene expression by binding to antioxidant response elements in their promoter regions. Thus, we uncovered the transcriptional control loop regulating human proteasome-dependent protein degradation to counteract proteotoxic stress caused by proteasome inhibition.

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

“…NRF1 was identified as the critical transcription factor for this type of regulation (45,46). Accordingly, in silico analysis of the PA200 promoter indicated one potential, highly evolutionary conserved NRF1 binding site close to the transcription start site, whereas only one poorly conserved binding site was detected in the extended promoter region of PA28␥.…”

“…4C). NRF1 has been described as the critical transcription factor for regulation of proteasomal gene expression in response to proteasome inhibition (45,46). A highly conserved NRF1 binding site was identified in close proximity to the transcription start of the PSME4 promoter (gene name of PA200).…”

Inflammatory Macrophages Induce Nrf2 Transcription Factor-dependent Proteasome Activity in Colonic NCM460 Cells and Thereby Confer Anti-apoptotic Protection

“…toward oxidative stress (33) caused by ROS production during inflammation. This property discriminates Nrf2 from Nrf1, which rather constitutively drives proteasomal gene expression and mediates compensation of a dampened proteasome activity under the influence of proteasome inhibitors (31,32). Because persistent oxidative stress is particularly present during chronic inflammation (2,3,38), the inducible proteasome activity under the control of Nrf2 plays a predominant role here and contributes to inflammation-associated carcinogenesis.…”

“…Whereas this proteasome inducing effect of Nrf2 in response to oxidative and electrophilic stress has been widely reported already (11,(25)(26)(27)(28)(29)(30), recent data revealed that the closely related transcription factor Nrf1 (TCF11) plays a particular role in the maintenance of constitutive proteasome activity (31). Moreover, Nrf1 mediates the inducing effect of proteasome inhibitors on proteasomal gene expression to a greater extent than Nrf2 (31,32). Thus, Nrf1 is regarded as modulator of basal proteasomal gene expression and proteasome activity, whereas Nrf2 is believed to mediate the induced proteasomal gene expression and proteasome activity (33), particularly in response to electrophilic and oxidative stress (34).…”

Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response

“…Perhaps best known among these are the heat shock response and the unfolded protein response. A third important and evolutionarily conserved proteotoxic stress response is mediated by the transcription factor Rpn4 (12)(13)(14)(15). Its best characterized function is to carry out the concerted transcriptional regulation of all proteasome genes (13).…”