PMID- 26731412
OWN - NLM
STAT- MEDLINE
DCOM- 20160630
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 1
DP  - 2016
TI  - Reversible Cysteine Acylation Regulates the Activity of Human Palmitoyl-Protein 
      Thioesterase 1 (PPT1).
PG  - e0146466
LID - 10.1371/journal.pone.0146466 [doi]
LID - e0146466
AB  - Mutations in the depalmitoylating enzyme gene, PPT1, cause the infantile form of 
      Neuronal Ceroid Lipofuscinosis (NCL), an early onset neurodegenerative disease. 
      During recent years there have been different therapeutic attempts including 
      enzyme replacement. Here we show that PPT1 is palmitoylated in vivo and is a 
      substrate for two palmitoylating enzymes, DHHC3 and DHHC7. The palmitoylated 
      protein is detected in both cell lysates and medium. The presence of PPT1 with 
      palmitoylated signal peptide in the cell medium suggests that a subset of the 
      protein is secreted by a nonconventional mechanism. Using a mutant form of PPT1, 
      C6S, which was not palmitoylated, we further demonstrate that palmitoylation does 
      not affect intracellular localization but rather that the unpalmitoylated form 
      enhanced the depalmitoylation activity of the protein. The calculated Vmax of the 
      enzyme was significantly affected by the palmitoylation, suggesting that the 
      addition of a palmitate group is reminiscent of adding a noncompetitive 
      inhibitor. Thus, we reveal the existence of a positive feedback loop, where 
      palmitoylation of PPT1 results in decreased activity and subsequent elevation in 
      the amount of palmitoylated proteins. This positive feedback loop is likely to 
      initiate a vicious cycle, which will enhance disease progression. The 
      understanding of this process may facilitate enzyme replacement strategies.
FAU - Segal-Salto, Michal
AU  - Segal-Salto M
AD  - The Department of Molecular Genetics, Weizmann Institute of Science, 76100 
      Rehovot, Israel.
FAU - Sapir, Tamar
AU  - Sapir T
AD  - The Department of Molecular Genetics, Weizmann Institute of Science, 76100 
      Rehovot, Israel.
FAU - Reiner, Orly
AU  - Reiner O
AD  - The Department of Molecular Genetics, Weizmann Institute of Science, 76100 
      Rehovot, Israel.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160105
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Acylation
MH  - Cysteine/*metabolism
MH  - Humans
MH  - Mutation
MH  - Neuronal Ceroid-Lipofuscinoses/genetics/metabolism
MH  - Neurons/*metabolism
MH  - Thiolester Hydrolases/genetics/*metabolism
PMC - PMC4701722
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/01/06 06:00
MHDA- 2016/07/01 06:00
PMCR- 2016/01/05
CRDT- 2016/01/06 06:00
PHST- 2015/08/04 00:00 [received]
PHST- 2015/12/17 00:00 [accepted]
PHST- 2016/01/06 06:00 [entrez]
PHST- 2016/01/06 06:00 [pubmed]
PHST- 2016/07/01 06:00 [medline]
PHST- 2016/01/05 00:00 [pmc-release]
AID - PONE-D-15-34210 [pii]
AID - 10.1371/journal.pone.0146466 [doi]
PST - epublish
SO  - PLoS One. 2016 Jan 5;11(1):e0146466. doi: 10.1371/journal.pone.0146466. 
      eCollection 2016.