PMID- 30737280
OWN - NLM
STAT- MEDLINE
DCOM- 20191016
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 294
IP  - 16
DP  - 2019 Apr 19
TI  - Stereoselective fatty acylation is essential for the release of lipidated WNT 
      proteins from the acyltransferase Porcupine (PORCN).
PG  - 6273-6282
LID - 10.1074/jbc.RA118.007268 [doi]
AB  - The maintenance of adult animal tissues depends upon highly conserved 
      intercellular signaling molecules that include the secreted WNT proteins. 
      Although it is generally accepted that lipidation of WNTs by the acyltransferase 
      Porcupine (PORCN) and their subsequent recognition by the Wntless (WLS) protein 
      is essential for their cellular secretion, the molecular understanding of this 
      process remains limited. Using structurally diverse fatty acyl donor analogs and 
      mouse embryonic fibroblasts expressing PORCN protein from different metazoan 
      phyla, we demonstrate here that PORCN active-site features, which are conserved 
      across the animal kingdom, enforce cis-Delta9 fatty acylation of WNTs. Aberrant 
      acylation of a WNT with an exogenously supplied trans-Delta9 fatty acid induced the 
      accumulation of WNT-PORCN complexes, suggesting that the fatty acyl species is 
      critical for the extrication of lipidated WNTs from PORCN. Our findings reveal a 
      previously unrecognized fatty acyl-selective checkpoint in the manufacturing of a 
      lipoprotein that forms a basis for WNT signaling sensitivity to trans fats and to 
      PORCN inhibitors in clinical development.
CI  - (c) 2019 Tuladhar et al.
FAU - Tuladhar, Rubina
AU  - Tuladhar R
AUID- ORCID: 0000-0001-6542-2368
AD  - From the Departments of Cell Biology.
FAU - Yarravarapu, Nageswari
AU  - Yarravarapu N
AD  - From the Departments of Cell Biology.
FAU - Ma, Yuyong
AU  - Ma Y
AD  - Biochemistry, and.
FAU - Zhang, Chengwei
AU  - Zhang C
AD  - Biochemistry, and.
FAU - Herbert, Jeremiah
AU  - Herbert J
AD  - From the Departments of Cell Biology.
FAU - Kim, James
AU  - Kim J
AUID- ORCID: 0000-0002-2992-9222
AD  - Internal Medicine and james.kim@utsouthwestern.edu.
AD  - Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern 
      Medical Center, Dallas, Texas 75390.
FAU - Chen, Chuo
AU  - Chen C
AD  - Biochemistry, and chuo.chen@utsouthwestern.edu.
FAU - Lum, Lawrence
AU  - Lum L
AD  - From the Departments of Cell Biology, lawrence.lum@utsouthwestern.edu.
LA  - eng
GR  - R01 CA168761/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190208
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Fatty Acids)
RN  - 0 (Membrane Proteins)
RN  - EC 2.3.- (Acyltransferases)
SB  - IM
MH  - Acylation
MH  - Acyltransferases/genetics/*metabolism
MH  - Animals
MH  - COS Cells
MH  - Caenorhabditis elegans
MH  - Chickens
MH  - Chlorocebus aethiops
MH  - Fatty Acids/genetics/*metabolism
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - *Protein Processing, Post-Translational
MH  - Schistosoma mansoni
MH  - *Wnt Signaling Pathway
MH  - Xenopus
PMC - PMC6484125
OTO - NOTNLM
OT  - Porcupine (PORCN)
OT  - Wnt pathway
OT  - Wnt signaling
OT  - Wntless (WLS)
OT  - acyltransferase
OT  - fatty acid
OT  - fatty acylation
OT  - membrane-bound O-acyltransferase (MBOAT)
OT  - palmitoleation
OT  - posttranslational modification (PTM)
OT  - signal transduction
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article. The content is solely the responsibility of the authors and does 
      not necessarily represent the official views of the National Institutes of Health
EDAT- 2019/02/10 06:00
MHDA- 2019/10/17 06:00
PMCR- 2020/04/19
CRDT- 2019/02/10 06:00
PHST- 2018/12/20 00:00 [received]
PHST- 2019/02/08 00:00 [revised]
PHST- 2019/02/10 06:00 [pubmed]
PHST- 2019/10/17 06:00 [medline]
PHST- 2019/02/10 06:00 [entrez]
PHST- 2020/04/19 00:00 [pmc-release]
AID - S0021-9258(20)36286-4 [pii]
AID - RA118.007268 [pii]
AID - 10.1074/jbc.RA118.007268 [doi]
PST - ppublish
SO  - J Biol Chem. 2019 Apr 19;294(16):6273-6282. doi: 10.1074/jbc.RA118.007268. Epub 
      2019 Feb 8.