PMID- 28808322
OWN - NLM
STAT- MEDLINE
DCOM- 20190306
LR  - 20211204
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Aug 14
TI  - Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum 
      stress, autophagy activation and disrupting ERAD activation.
PG  - 8100
LID - 10.1038/s41598-017-08722-3 [doi]
LID - 8100
AB  - Proteostasis alteration and neuroinflammation are typical features of normal 
      aging. We have previously shown that neuroinflammation alters cellular 
      proteostasis through immunoproteasome induction, leading to a transient decrease 
      of proteasome activity. Here, we further investigated the role of acute 
      lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular 
      proteostasis. In particular, we focused on macroautophagy (hereinafter called 
      autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We 
      demonstrate that LPS injection induced autophagy activation that was dependent, 
      at least in part, on glycogen synthase kinase (GSK)-3beta activity but independent 
      of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also 
      produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein 
      response (UPR) activation with a rapid activating transcription factor (ATF) 6alpha 
      attenuation that resulted in a time-dependent down-regulation of ERAD markers. In 
      this regard, the time-dependent accumulation of unspliced X-box binding protein 
      (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1alpha-mediated 
      splicing activity, might underlie in vivo ATF6alpha attenuation. Importantly, 
      lactacystin-induced activation of ERAD was abolished in both the acute 
      neuroinflammation model and in aged rats. Therefore, we provide a cellular 
      pathway through which neuroinflammation might sensitize cells to 
      neurodegeneration under stress situations, being relevant in normal aging and 
      other disorders where neuroinflammation is a characteristic feature.
FAU - Pintado, Cristina
AU  - Pintado C
AUID- ORCID: 0000-0002-9369-8318
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, 
      Universidad de Sevilla, 41012, Sevilla, Spain.
AD  - Facultad de Ciencias Ambientales y Bioquimica, Avenida Carlos III s/n, 45071, 
      Toledo, Spain.
FAU - Macias, Sandra
AU  - Macias S
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, 
      Universidad de Sevilla, 41012, Sevilla, Spain.
AD  - Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del 
      Rocio/Consejo Superior de Investigaciones Cientificas/Universidad de Sevilla, 
      41013, Sevilla, Spain.
FAU - Dominguez-Martin, Helena
AU  - Dominguez-Martin H
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, 
      Universidad de Sevilla, 41012, Sevilla, Spain.
AD  - Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del 
      Rocio/Consejo Superior de Investigaciones Cientificas/Universidad de Sevilla, 
      41013, Sevilla, Spain.
FAU - Castano, Angelica
AU  - Castano A
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, 
      Universidad de Sevilla, 41012, Sevilla, Spain.
AD  - Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del 
      Rocio/Consejo Superior de Investigaciones Cientificas/Universidad de Sevilla, 
      41013, Sevilla, Spain.
FAU - Ruano, Diego
AU  - Ruano D
AD  - Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, 
      Universidad de Sevilla, 41012, Sevilla, Spain. ruano@us.es.
AD  - Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del 
      Rocio/Consejo Superior de Investigaciones Cientificas/Universidad de Sevilla, 
      41013, Sevilla, Spain. ruano@us.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170814
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (X-Box Binding Protein 1)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
SB  - IM
MH  - Activating Transcription Factor 6/metabolism
MH  - Animals
MH  - Autophagy/*physiology
MH  - Cell Line
MH  - Down-Regulation/physiology
MH  - Endoplasmic Reticulum Stress/*physiology
MH  - Endoplasmic Reticulum-Associated Degradation/*physiology
MH  - Endoribonucleases/metabolism
MH  - Glycogen Synthase Kinase 3 beta/metabolism
MH  - Inflammation/metabolism/*physiopathology
MH  - Male
MH  - Mice
MH  - Proteostasis/*physiology
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Unfolded Protein Response/physiology
MH  - X-Box Binding Protein 1/metabolism
PMC - PMC5556015
COIS- The authors declare that they have no competing interests.
EDAT- 2017/08/16 06:00
MHDA- 2019/03/07 06:00
PMCR- 2017/08/14
CRDT- 2017/08/16 06:00
PHST- 2016/12/07 00:00 [received]
PHST- 2017/07/14 00:00 [accepted]
PHST- 2017/08/16 06:00 [entrez]
PHST- 2017/08/16 06:00 [pubmed]
PHST- 2019/03/07 06:00 [medline]
PHST- 2017/08/14 00:00 [pmc-release]
AID - 10.1038/s41598-017-08722-3 [pii]
AID - 8722 [pii]
AID - 10.1038/s41598-017-08722-3 [doi]
PST - epublish
SO  - Sci Rep. 2017 Aug 14;7(1):8100. doi: 10.1038/s41598-017-08722-3.