PMID- 33166339
OWN - NLM
STAT- MEDLINE
DCOM- 20210108
LR  - 20220211
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 15
IP  - 11
DP  - 2020
TI  - Regulation of inflammatory signaling by the ST6Gal-I sialyltransferase.
PG  - e0241850
LID - 10.1371/journal.pone.0241850 [doi]
LID - e0241850
AB  - The ST6Gal-I sialyltransferase, an enzyme that adds alpha2-6-linked sialic acids to 
      N-glycosylated proteins, regulates multiple immunological processes. However, the 
      contribution of receptor sialylation to inflammatory signaling has been 
      under-investigated. In the current study, we uncovered a role for ST6Gal-I in 
      promoting sustained signaling through two prominent inflammatory pathways, NFkappaB 
      and JAK/STAT. Using the U937 monocytic cell model, we determined that knockdown 
      (KD) of ST6Gal-I expression had no effect on the rapid activation of NFkappaB by TNF 
      (</= 30 min), whereas long-term TNF-induced NFkappaB activation (2-6 hr) was diminished 
      in ST6Gal-I-KD cells. These data align with prior work in epithelial cells 
      showing that alpha2-6 sialylation of TNFR1 prolongs TNF-dependent NFkappaB activation. 
      Similar to TNF, long-term, but not short-term, LPS-induced activation of NFkappaB was 
      suppressed by ST6Gal-I KD. ST6Gal-I KD cells also exhibited reduced long-term 
      IRF3 and STAT3 activation by LPS. Given that ST6Gal-I activity modulated 
      LPS-dependent signaling, we conducted pull-down assays using SNA (a lectin 
      specific for alpha2-6 sialic acids) to show that the LPS receptor, TLR4, is a 
      substrate for sialylation by ST6Gal-I. We next assessed signaling by IFNgamma, IL-6 
      and GM-CSF, and found that ST6Gal-I-KD had a limited effect on STAT activation 
      induced by these cytokines. To corroborate these findings, signaling was 
      monitored in bone marrow derived macrophages (BMDMs) from mice with 
      myeloid-specific deletion of ST6Gal-I (LysMCre/ST6Gal-Ifl/fl). In agreement with 
      data from U937 cells, BMDMs with ST6Gal-I knockout displayed reduced long-term 
      activation of NFkappaB by both TNF and LPS, and diminished long-term LPS-dependent 
      STAT3 activation. However, STAT activation induced by IFNgamma, IL-6 and GM-CSF was 
      comparable in wild-type and ST6Gal-I knockout BMDMs. These results implicate 
      ST6Gal-I-mediated receptor sialylation in prolonging the activity of select 
      signaling cascades including TNF/NFkappaB, LPS/NFkappaB, and LPS/STAT3, providing new 
      insights into ST6Gal-I's role in modulating the inflammatory phenotype of 
      monocytic cells.
FAU - Holdbrooks, Andrew T
AU  - Holdbrooks AT
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      at Birmingham, Birmingham, AL, United States of America.
FAU - Ankenbauer, Katherine E
AU  - Ankenbauer KE
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      at Birmingham, Birmingham, AL, United States of America.
FAU - Hwang, Jihye
AU  - Hwang J
AUID- ORCID: 0000-0001-8224-0240
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      at Birmingham, Birmingham, AL, United States of America.
FAU - Bellis, Susan L
AU  - Bellis SL
AUID- ORCID: 0000-0002-5071-527X
AD  - Department of Cell, Developmental and Integrative Biology, University of Alabama 
      at Birmingham, Birmingham, AL, United States of America.
LA  - eng
GR  - R01 CA225177/CA/NCI NIH HHS/United States
GR  - T32 GM008111/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20201109
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, CD)
RN  - 0 (NF-kappa B)
RN  - 0 (STAT Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.4.99.- (Sialyltransferases)
RN  - EC 2.4.99.1 (ST6GAL1 protein, human)
SB  - IM
MH  - Animals
MH  - Antigens, CD/*genetics
MH  - Cell Line
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Macrophages/drug effects/metabolism
MH  - Mice
MH  - Monocytes/drug effects/metabolism
MH  - NF-kappa B/metabolism
MH  - STAT Transcription Factors/metabolism
MH  - Sialyltransferases/*genetics
MH  - Signal Transduction/*drug effects
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC7652342
COIS- The authors have declared that no competing interests exist
EDAT- 2020/11/10 06:00
MHDA- 2021/01/09 06:00
PMCR- 2020/11/09
CRDT- 2020/11/09 17:12
PHST- 2020/02/25 00:00 [received]
PHST- 2020/10/21 00:00 [accepted]
PHST- 2020/11/09 17:12 [entrez]
PHST- 2020/11/10 06:00 [pubmed]
PHST- 2021/01/09 06:00 [medline]
PHST- 2020/11/09 00:00 [pmc-release]
AID - PONE-D-20-05465 [pii]
AID - 10.1371/journal.pone.0241850 [doi]
PST - epublish
SO  - PLoS One. 2020 Nov 9;15(11):e0241850. doi: 10.1371/journal.pone.0241850. 
      eCollection 2020.