start-ver=1.4
cd-journal=joma
no-vol=524
cd-vols=
no-issue=4
article-no=
start-page=910
end-page=915
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200416
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=S-Nitrosylation at the active site decreases the ubiquitin-conjugating activity of ubiquitin-conjugating enzyme E2 D1 (UBE2D1), an ERAD-associated protein
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=S-Nitrosylation of protein cysteine thiol is a post-translational modification mediated by nitric oxide (NO). The overproduction of NO causes nitrosative stress, which is known to induce endoplasmic reticulum (ER) stress. We previously reported that S-nitrosylation of protein disulfide isomerase (PDI) and the ER stress sensor inositol-requiring enzyme 1 (IRE1) decreases their enzymatic activities. However, it remains unclear whether nitrosative stress affects ER-associated degradation (ERAD), a separate ER stress regulatory system responsible for the degradation of substrates via the ubiquitin-proteasomal pathway.

In the present study, we found that the ubiquitination of a known ERAD substrate, serine/threonine-protein kinase 1 (SGK1), is attenuated by nitrosative stress. C-terminus of Hsc70-interacting protein (CHIP) together with ubiquitin-conjugating enzyme E2 D1 (UBE2D1) are involved in this modification. We detected that UBE2D1 is S-nitrosylated at its active site, Cys85 by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, in vitro and cell-based experiments revealed that S-nitrosylated UBE2D1 has decreased ubiquitin-conjugating activity.

Our results suggested that nitrosative stress interferes with ERAD, leading to prolongation of ER stress by co-disruption of various pathways, including the molecular chaperone and ER stress sensor pathways. Given that nitrosative stress and ER stress are upregulated in the brains of patient with Parkinson’s disease (PD) and of those with Alzheimer’s disease (AD), our findings may provide further insights into the pathogenesis of these neurodegenerative disorders.
en-copyright=
kn-copyright=

en-aut-name=FujikawaKana
en-aut-sei=Fujikawa
en-aut-mei=Kana
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NakaharaKengo
en-aut-sei=Nakahara
en-aut-mei=Kengo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TakasugiNobumasa
en-aut-sei=Takasugi
en-aut-mei=Nobumasa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NishiyaTadashi
en-aut-sei=Nishiya
en-aut-mei=Tadashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=ItoAkihiro
en-aut-sei=Ito
en-aut-mei=Akihiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=UchidaKoji
en-aut-sei=Uchida
en-aut-mei=Koji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=UeharaTakashi
en-aut-sei=Uehara
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=School of Pharmaceutical Sciences, Ohu University
kn-affil=

affil-num=5
en-affil=School of Life Sciences, Tokyo University of Pharmacy and Life Sciences
kn-affil=

affil-num=6
en-affil=Laboratory of Food Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo
kn-affil=

affil-num=7
en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=Nitric oxide
kn-keyword=Nitric oxide
en-keyword=Redox
kn-keyword=Redox
en-keyword=Endoplasmic reticulum (ER) stress
kn-keyword=Endoplasmic reticulum (ER) stress
en-keyword=ER-Associated degradation
kn-keyword=ER-Associated degradation
en-keyword=Ubiquitin proteasome system
kn-keyword=Ubiquitin proteasome system
en-keyword=Ubiquitin-conjugating enzyme E2
kn-keyword=Ubiquitin-conjugating enzyme E2
END