Nrf1 can be processed and activated in a proteasome-independent manner.
In response to proteasome inhibition, the transcription factor Nrf1 facilitates de novo synthesis of proteasomes by inducing proteasome subunit (PSM) genes [1,2]. Previously, we showed that activation of the p120 form of Nrf1, a membrane-bound protein in the endoplasmic reticulum (ER) with the bulk of its polypeptide in the lumen, involves its retrotranslocation into the cytosol in a manner that depends on the AAA-ATPase p97/VCP [3]. This is followed by proteolytic processing and mobilization of the transcriptionally active p110 form of Nrf1 to the nucleus. A subsequent study suggested that site-specific proteolytic processing of Nrf1 by the proteasome yields an active 75 kDa fragment [4]. We show here that under conditions where all three active sites of the proteasome are completely blocked, p120 Nrf1 can still be proteolytically cleaved to the p110 form, which is translocated to the nucleus to activate transcription of PSM genes. Thus, our results indicate that a proteasome-independent pathway can promote the release of active p110 Nrf1 from the ER membrane.
Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Janakiram R
JR
Vangala
Institut für Biochemie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Franziska
F
Sotzny
Institut für Biochemie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Elke
E
Krüger
Division of Biology and Biological Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
Raymond J
RJ
Deshaies
Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: senthil.radhakrishnan@vcuhealth.org.
Senthil K
SK
Radhakrishnan
D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*
C495633:NRF1 protein, human; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
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