GPCR/endocytosis/ERK signaling/S2R is involved in the regulation of the internalization, mitochondria-targeting and -activating properties of human salivary histatin 1.
Journal
International journal of oral science
ISSN: 2049-3169
Titre abrégé: Int J Oral Sci
Pays: India
ID NLM: 101504351
Informations de publication
Date de publication:
15 08 2022
15 08 2022
Historique:
received:
27
12
2021
accepted:
10
05
2022
revised:
14
04
2022
entrez:
15
8
2022
pubmed:
16
8
2022
medline:
18
8
2022
Statut:
epublish
Résumé
Human salivary histatin 1 (Hst1) exhibits a series of cell-activating properties, such as promoting cell spreading, migration, and metabolic activity. We recently have shown that fluorescently labeled Hst1 (F-Hst1) targets and activates mitochondria, presenting an important molecular mechanism. However, its regulating signaling pathways remain to be elucidated. We investigated the influence of specific inhibitors of G protein-coupled receptors (GPCR), endocytosis pathways, extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, p38 signaling, mitochondrial respiration and Na+/K+-ATPase activity on the uptake, mitochondria-targeting and -activating properties of F-Hst1. We performed a siRNA knockdown (KD) to assess the effect of Sigma-2 receptor (S2R) /Transmembrane Protein 97 (TMEM97)-a recently identified target protein of Hst1. We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1. Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1. The inhibitors of GPCR, ERK1/2, phagocytosis, and clathrin-mediated endocytosis (CME) as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake, which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity. Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1. We further showed the intracellular trafficking and targeting process of F-Hst1, in which early endosome plays an important role. Overall, phagocytosis, CME, GPCR, ERK signaling, and S2R/TMEM97 are involved in the internalization of Hst1, while only CME and S2R/TMEM97 are critical for its subcellular targeting. The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.
Identifiants
pubmed: 35970844
doi: 10.1038/s41368-022-00181-5
pii: 10.1038/s41368-022-00181-5
pmc: PMC9378733
doi:
Substances chimiques
Histatins
0
Membrane Proteins
0
RNA, Small Interfering
0
Receptors, G-Protein-Coupled
0
Receptors, sigma
0
TMEM97 protein, human
0
sigma-2 receptor
0
HTN1 protein, human
101056-53-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
42Informations de copyright
© 2022. The Author(s).
Références
PLoS Pathog. 2008 Oct;4(10):e1000190
pubmed: 18974864
Curr Opin Cell Biol. 2014 Apr;27:109-16
pubmed: 24680436
Traffic. 2000 Sep;1(9):695-701
pubmed: 11208157
Biomaterials. 2009 Aug;30(23-24):3934-45
pubmed: 19403166
Circ Res. 2002 Mar 8;90(4):390-7
pubmed: 11884367
Small. 2011 May 23;7(10):1322-37
pubmed: 21520409
Mol Biol Cell. 2006 Feb;17(2):645-57
pubmed: 16314390
FASEB J. 2008 Nov;22(11):3805-12
pubmed: 18650243
Mol Biol Cell. 1999 Apr;10(4):961-74
pubmed: 10198050
J Cell Sci. 2008 Oct 15;121(Pt 20):3445-58
pubmed: 18827013
FASEB J. 2011 Aug;25(8):2650-8
pubmed: 21525488
Cold Spring Harb Perspect Biol. 2014 Oct 23;6(11):a022616
pubmed: 25341920
J Biol Chem. 1999 Mar 12;274(11):7286-91
pubmed: 10066791
Cells. 2020 Mar 26;9(4):
pubmed: 32225006
Nat Rev Mol Cell Biol. 2007 Aug;8(8):603-12
pubmed: 17609668
Science. 1998 Jun 12;280(5370):1723-9
pubmed: 9624044
J Tissue Eng Regen Med. 2021 Apr;15(4):336-346
pubmed: 33480156
Arch Oral Biol. 1990;35(2):137-43
pubmed: 2344289
J Cell Biol. 1993 Dec;123(5):1107-17
pubmed: 8245121
Cell. 2004 Feb 6;116(3):445-56
pubmed: 15016378
Annu Rev Biochem. 2009;78:857-902
pubmed: 19317650
Biochem J. 2004 Jul 15;381(Pt 2):447-52
pubmed: 15109304
Am J Physiol Lung Cell Mol Physiol. 2003 Mar;284(3):L501-7
pubmed: 12573988
J Cell Biol. 2000 Mar 20;148(6):1267-81
pubmed: 10725339
Cell. 2004 Jun 11;117(6):699-711
pubmed: 15186772
J Dent Res. 2017 Apr;96(4):430-436
pubmed: 27941125
J Immunol. 2008 Jun 1;180(11):7485-96
pubmed: 18490749
PLoS One. 2020 May 1;15(5):e0232532
pubmed: 32357161
J Mol Cell Biol. 2018 Dec 1;10(6):539-548
pubmed: 30383243
FEBS J. 2021 Dec;288(23):6815-6827
pubmed: 34233061
J Cell Biol. 2003 May 26;161(4):673-7
pubmed: 12771123
BMC Biochem. 2017 Mar 6;18(1):3
pubmed: 28264651
Science. 1998 Jun 12;280(5370):1763-6
pubmed: 9624056
J Dent Res. 2009 Sep;88(9):846-50
pubmed: 19767583
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
FASEB J. 2017 Nov;31(11):4946-4958
pubmed: 28751526
J Pharmacol Exp Ther. 2016 Feb;356(2):232-43
pubmed: 26574517
Biochim Biophys Acta. 2009 Nov;1787(11):1309-16
pubmed: 19413950
Free Radic Biol Med. 2005 Jan 1;38(1):2-11
pubmed: 15589366
Cell Death Dis. 2018 Mar 9;9(3):388
pubmed: 29523782
FASEB J. 2015 Aug;29(8):3124-32
pubmed: 25903106
Mol Biol Cell. 2013 Nov;24(21):3420-34
pubmed: 24006491
NPJ Syst Biol Appl. 2021 Jun 2;7(1):26
pubmed: 34078916
Gut. 1979 May;20(5):356-65
pubmed: 223948
Biochem Res Int. 2020 Feb 11;2020:4186308
pubmed: 32104603
Physiol Rev. 2005 Oct;85(4):1159-204
pubmed: 16183910
Nat Rev Drug Discov. 2010 Aug;9(8):615-27
pubmed: 20616808
Cell Prolif. 2021 Aug;54(8):e13087
pubmed: 34255393
Mol Cancer Ther. 2013 Oct;12(10):1925-34
pubmed: 24072884
FASEB J. 2017 Sep;31(9):3922-3933
pubmed: 28522595
Infect Immun. 2010 Feb;78(2):865-71
pubmed: 19933834
Nature. 2009 May 21;459(7245):356-63
pubmed: 19458711
Nat Rev Mol Cell Biol. 2001 Feb;2(2):107-17
pubmed: 11252952
Biochem J. 2004 May 1;379(Pt 3):665-72
pubmed: 14733612
J Cell Biol. 1994 Dec;127(5):1199-215
pubmed: 7962085
Nature. 2003 Mar 6;422(6927):37-44
pubmed: 12621426
J Cell Biol. 2010 Feb 22;188(4):547-63
pubmed: 20156964
FEBS Open Bio. 2020 Mar;10(3):396-406
pubmed: 31957262
FASEB J. 2009 Nov;23(11):3928-35
pubmed: 19652025
Bioorg Med Chem Lett. 1998 Oct 20;8(20):2839-44
pubmed: 9873633
J Cell Biol. 2016 Sep 26;214(7):831-45
pubmed: 27646275
Life Sci. 2019 Jun 15;227:129-136
pubmed: 31002922
Cell. 2005 May 6;121(3):437-50
pubmed: 15882625
J Biol Chem. 2007 Jun 29;282(26):18831-41
pubmed: 17485465
PLoS One. 2017 May 23;12(5):e0178030
pubmed: 28542418
J Cell Biol. 2006 Feb 13;172(4):605-18
pubmed: 16476778
Nat Cell Biol. 1999 Oct;1(6):376-82
pubmed: 10559966
FEBS Open Bio. 2020 Aug;10(8):1503-1515
pubmed: 32484586
Beilstein J Nanotechnol. 2020 Jan 9;11:101-123
pubmed: 31976201
Toxins (Basel). 2011 Jul;3(7):884-99
pubmed: 22069745