PMID- 28900035
OWN - NLM
STAT- MEDLINE
DCOM- 20181029
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 292
IP  - 46
DP  - 2017 Nov 17
TI  - Prion protein is required for tumor necrosis factor alpha (TNFalpha)-triggered nuclear 
      factor kappaB (NF-kappaB) signaling and cytokine production.
PG  - 18747-18759
LID - 10.1074/jbc.M117.787283 [doi]
AB  - The expression of normal cellular prion protein (PrP) is required for the 
      pathogenesis of prion diseases. However, the physiological functions of PrP 
      remain ambiguous. Here, we identified PrP as being critical for tumor necrosis 
      factor (TNF) alpha-triggered signaling in a human melanoma cell line, M2, and a 
      pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFalpha 
      up-regulates the expression of p-IkappaB-kinase alpha/beta (p-IKKalpha/beta), p-p65, and p-JNK, but 
      down-regulates the IkappaBalpha protein, all of which are downstream signaling 
      intermediates in the TNF receptor signaling cascade. When PRNP is deleted in M2 
      cells, the effects of TNFalpha are no longer detectable. More importantly, p-p65 and 
      p-JNK responses are restored when PRNP is reintroduced into the PRNP null cells. 
      TNFalpha also activates NF-kappaB and increases TNFalpha production in wild-type M2 cells, 
      but not in PrP-null M2 cells. Similar results are obtained in the BxPC-3 cells. 
      Moreover, TNFalpha activation of NF-kappaB requires ubiquitination of 
      receptor-interacting serine/threonine kinase 1 (RIP1) and TNF receptor-associated 
      factor 2 (TRAF2). TNFalpha treatment increases the binding between PrP and the 
      deubiquitinase tumor suppressor cylindromatosis (CYLD), in these treated cells, 
      binding of CYLD to RIP1 and TRAF2 is reduced. We conclude that PrP traps CYLD, 
      preventing it from binding and deubiquitinating RIP1 and TRAF2. Our findings 
      reveal that PrP enhances the responses to TNFalpha, promoting proinflammatory 
      cytokine production, which may contribute to inflammation and tumorigenesis.
CI  - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Wu, Gui-Ru
AU  - Wu GR
AUID- ORCID: 0000-0002-4946-7854
AD  - From the Wuhan Institute of Virology, Chinese Academy of Sciences, State Key 
      Laboratory of Virology, 44 Xiao Hong Shan Zhong Qu, Wuhan 430071, China.
AD  - the University of Chinese Academy of Sciences, Beijing 100000, China.
FAU - Mu, Tian-Chen
AU  - Mu TC
AUID- ORCID: 0000-0002-0271-0941
AD  - the Department of Life Sciences, Wuhan University, Wuhan 430010, China.
FAU - Gao, Zhen-Xing
AU  - Gao ZX
AUID- ORCID: 0000-0002-2692-985X
AD  - From the Wuhan Institute of Virology, Chinese Academy of Sciences, State Key 
      Laboratory of Virology, 44 Xiao Hong Shan Zhong Qu, Wuhan 430071, China.
FAU - Wang, Jun
AU  - Wang J
AD  - From the Wuhan Institute of Virology, Chinese Academy of Sciences, State Key 
      Laboratory of Virology, 44 Xiao Hong Shan Zhong Qu, Wuhan 430071, China.
FAU - Sy, Man-Sun
AU  - Sy MS
AD  - the Department of Pathology, Case Western Reserve University, Cleveland, Ohio 
      44106, and.
FAU - Li, Chao-Yang
AU  - Li CY
AUID- ORCID: 0000-0003-3582-4141
AD  - From the Wuhan Institute of Virology, Chinese Academy of Sciences, State Key 
      Laboratory of Virology, 44 Xiao Hong Shan Zhong Qu, Wuhan 430071, China, 
      cyli@wh.iov.cn.
AD  - the Wuhan Brain Hospital, No. 5 Huiji Road, Jiang'an District, Wuhan 430010, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170912
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - 0 (Prion Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.19.12 (CYLD protein, human)
RN  - EC 3.4.19.12 (Deubiquitinating Enzyme CYLD)
SB  - IM
MH  - Carcinogenesis/*immunology
MH  - Carcinoma, Pancreatic Ductal/immunology
MH  - Cell Line, Tumor
MH  - Cytokines/*immunology
MH  - Deubiquitinating Enzyme CYLD/immunology
MH  - Humans
MH  - Melanoma/immunology
MH  - NF-kappa B/*immunology
MH  - Pancreatic Neoplasms/immunology
MH  - Prion Proteins/*immunology
MH  - *Signal Transduction
MH  - Tumor Necrosis Factor-alpha/*immunology
PMC - PMC5704461
OTO - NOTNLM
OT  - CYLD
OT  - NF-kappaB (NF-kappaB)
OT  - NF-kappaB signaling
OT  - PrP
OT  - TNFalpha
OT  - deubiquitylation (deubiquitination)
OT  - melanoma
OT  - prion
OT  - tumor necrosis factor (TNF)
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2017/09/14 06:00
MHDA- 2018/10/30 06:00
PMCR- 2017/09/12
CRDT- 2017/09/14 06:00
PHST- 2017/03/21 00:00 [received]
PHST- 2017/09/10 00:00 [revised]
PHST- 2017/09/14 06:00 [pubmed]
PHST- 2018/10/30 06:00 [medline]
PHST- 2017/09/14 06:00 [entrez]
PHST- 2017/09/12 00:00 [pmc-release]
AID - S0021-9258(20)32923-9 [pii]
AID - M117.787283 [pii]
AID - 10.1074/jbc.M117.787283 [doi]
PST - ppublish
SO  - J Biol Chem. 2017 Nov 17;292(46):18747-18759. doi: 10.1074/jbc.M117.787283. Epub 
      2017 Sep 12.