PMID- 32357547
OWN - NLM
STAT- MEDLINE
DCOM- 20210402
LR  - 20230510
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 10
IP  - 5
DP  - 2020 Apr 26
TI  - Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced 
      Bioavailability of Latent TGFbeta in Mucolipidosis II Cells.
LID - 10.3390/biom10050670 [doi]
LID - 670
AB  - Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the 
      carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth 
      factor signaling has been identified as a contributor to the phenotypes 
      associated with ML-II and other lysosomal disorders but an understanding of how 
      these signaling pathways are affected is still emerging. Here, we investigated 
      transforming growth factor beta 1 (TGFbeta1) signaling in the context of ML-II 
      patient fibroblasts, observing decreased TGFbeta1 signaling that was accompanied by 
      impaired TGFbeta1-dependent wound closure. We found increased intracellular latent 
      TGFbeta1 complexes, caused by reduced secretion and stable localization in 
      detergent-resistant lysosomes. Sortilin, a sorting receptor for hydrolases and 
      TGFbeta-related cytokines, was upregulated in ML-II fibroblasts as well as 
      GNPTAB-null HeLa cells, suggesting a mechanism for inappropriate lysosomal 
      targeting of TGFbeta. Co-expression of sortilin and TGFbeta in HeLa cells resulted in 
      reduced TGFbeta1 secretion. Elevated sortilin levels correlated with normal levels 
      of cathepsin D in ML-II cells, consistent with a compensatory role for this 
      receptor in lysosomal hydrolase targeting. Collectively, these data support a 
      model whereby sortilin upregulation in cells with lysosomal storage maintains 
      hydrolase sorting but suppresses TGFbeta1 secretion through increased lysosomal 
      delivery. These findings highlight an unexpected link between impaired lysosomal 
      sorting and altered growth factor bioavailability.
FAU - Barnes, Jarrod W
AU  - Barnes JW
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama 
      at Birmingham, Birmingham, AL 35294, USA.
FAU - Aarnio-Peterson, Megan
AU  - Aarnio-Peterson M
AD  - Greenwood Genetic Center, Greenwood, SC 29646, USA.
FAU - Norris, Joy
AU  - Norris J
AD  - Greenwood Genetic Center, Greenwood, SC 29646, USA.
FAU - Haskins, Mark
AU  - Haskins M
AD  - Emeritus Professor, Pathology and Medical Genetics, School of Veterinary 
      Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051, USA.
FAU - Flanagan-Steet, Heather
AU  - Flanagan-Steet H
AD  - Greenwood Genetic Center, Greenwood, SC 29646, USA.
FAU - Steet, Richard
AU  - Steet R
AUID- ORCID: 0000-0002-0975-4963
AD  - Greenwood Genetic Center, Greenwood, SC 29646, USA.
LA  - eng
GR  - R00 HL131866/HL/NHLBI NIH HHS/United States
GR  - R01 GM086524/GM/NIGMS NIH HHS/United States
GR  - R01 NS128907/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200426
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups))
RN  - EC 2.7.8.15 (GNPTAB protein, human)
RN  - EC 3.4.23.5 (Cathepsin D)
RN  - Z020Y8WIJ4 (sortilin)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/*genetics/metabolism
MH  - Cathepsin D/metabolism
MH  - Cell Line
MH  - Cells, Cultured
MH  - Fibroblasts/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Lysosomes/metabolism
MH  - Mucolipidoses/*metabolism
MH  - Protein Transport
MH  - Signal Transduction
MH  - Transferases (Other Substituted Phosphate Groups)/genetics
MH  - Transforming Growth Factor beta/*metabolism
MH  - Up-Regulation
PMC - PMC7277838
OTO - NOTNLM
OT  - TGF-beta
OT  - cathepsin D
OT  - lysosomes
OT  - mucolipidosis II
OT  - sortilin
COIS- The authors declare no conflict of interest.
EDAT- 2020/05/03 06:00
MHDA- 2021/04/07 06:00
PMCR- 2020/05/01
CRDT- 2020/05/03 06:00
PHST- 2020/02/17 00:00 [received]
PHST- 2020/04/14 00:00 [revised]
PHST- 2020/04/20 00:00 [accepted]
PHST- 2020/05/03 06:00 [entrez]
PHST- 2020/05/03 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/05/01 00:00 [pmc-release]
AID - biom10050670 [pii]
AID - biomolecules-10-00670 [pii]
AID - 10.3390/biom10050670 [doi]
PST - epublish
SO  - Biomolecules. 2020 Apr 26;10(5):670. doi: 10.3390/biom10050670.