title: LIS1 regulates osteoclast formation and function through its interactions with dynein/dynactin and Plekhm1.
abstract: Microtubule organization and lysosomal secretion are both critical for the activation and function of osteoclasts, highly specialized polykaryons that are responsible for bone resorption and skeletal homeostasis. Here, we have identified a novel interaction between microtubule regulator LIS1 and Plekhm1, a lysosome-associated protein implicated in osteoclast secretion. Decreasing LIS1 expression by shRNA dramatically attenuated osteoclast formation and function, as shown by a decreased number of mature osteoclasts differentiated from bone marrow macrophages, diminished resorption pits formation, and reduced level of CTx-I, a bone resorption marker. The ablated osteoclast formation in LIS1-depleted macrophages was associated with a significant decrease in macrophage proliferation, osteoclast survival and differentiation, which were caused by reduced activation of ERK and AKT by M-CSF, prolonged RANKL-induced JNK activation and declined expression of NFAT-c1, a master transcription factor of osteoclast differentiation. Consistent with its critical role in microtubule organization and dynein function in other cell types, we found that LIS1 binds to and colocalizes with dynein in osteoclasts. Loss of LIS1 led to disorganized microtubules and aberrant dynein function. More importantly, the depletion of LIS1 in osteoclasts inhibited the secretion of Cathepsin K, a crucial lysosomal hydrolase for bone degradation, and reduced the motility of osteoclast precursors. These results indicate that LIS1 is a previously unrecognized regulator of osteoclast formation, microtubule organization, and lysosomal secretion by virtue of its ability to modulate dynein function and Plekhm1.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America.
authors.forename: Shiqiao
authors.initials: S
authors.lastname: Ye
authors.forename: Tristan W
authors.initials: TW
authors.lastname: Fowler
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Pavlos
authors.forename: Pei Ying
authors.initials: PY
authors.lastname: Ng
authors.forename: Kai
authors.initials: K
authors.lastname: Liang
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Feng
authors.forename: Minghao
authors.initials: M
authors.lastname: Zheng
authors.forename: Richard
authors.initials: R
authors.lastname: Kurten
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhao
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000071183:Autophagy-Related Proteins; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism* / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology*; D011485:Protein Binding; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; C570891:Plekhm1 protein, mouse; D033921:Vesicular Transport Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D056657:Cathepsin K; D004398:Dyneins
references.citation: Dev Cell. 2008 Mar;14(3):342-53
references.pmid: 18331715
references.citation: J Cell Biol. 2010 Jul 12;190(1):45-53
references.pmid: 20624900
references.citation: Biochem Biophys Res Commun. 2002 May 10;293(3):1060-5
references.pmid: 12051767
references.citation: Mol Cell Biol. 2002 May;22(9):3089-102
references.pmid: 11940666
references.citation: Mol Biol Cell. 2003 Feb;14(2):407-16
references.pmid: 12589043
references.citation: J Cell Sci. 2010 Jan 15;123(Pt 2):202-12
references.pmid: 20048338
references.citation: Eur J Biochem. 1996 Sep 1;240(2):400-7
references.pmid: 8841405
references.citation: Nat Cell Biol. 2010 Jun;12(6):598-604
references.pmid: 20473295
references.citation: J Cell Biol. 2007 Sep 10;178(6):1053-64
references.pmid: 17846174
references.citation: Endocr Rev. 1996 Aug;17(4):308-32
references.pmid: 8854048
references.citation: EMBO J. 2008 Oct 8;27(19):2471-83
references.pmid: 18784752
references.citation: Mol Endocrinol. 2005 Mar;19(3):771-80
references.pmid: 15591537
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6158-63
references.pmid: 15073337
references.citation: Nature. 2003 May 15;423(6937):337-42
references.pmid: 12748652
references.citation: Genes Dev. 2006 Jun 1;20(11):1384-93
references.pmid: 16751177
references.citation: Cell. 2007 Jan 12;128(1):71-83
references.pmid: 17218256
references.citation: Nat Genet. 1998 Aug;19(4):333-9
references.pmid: 9697693
references.citation: Dev Cell. 2002 Dec;3(6):889-901
references.pmid: 12479813
references.citation: J Cell Biochem. 2003 Dec 1;90(5):871-83
references.pmid: 14624447
references.citation: J Clin Invest. 2010 Jun;120(6):1981-93
references.pmid: 20501942
references.citation: J Clin Invest. 2007 Apr;117(4):919-30
references.pmid: 17404618
references.citation: Genes Dev. 2001 Mar 15;15(6):639-51
references.pmid: 11274050
references.citation: Exp Cell Res. 1999 Sep 15;251(2):477-91
references.pmid: 10471332
references.citation: J Bone Miner Res. 2008 Mar;23(3):380-91
references.pmid: 17997709
references.citation: PLoS One. 2007 Jan 31;2(1):e179
references.pmid: 17264882
references.citation: J Cell Sci. 2000 Feb;113 ( Pt 3):377-81
references.pmid: 10639325
references.citation: Nat Rev Mol Cell Biol. 2009 Dec;10(12):854-65
references.pmid: 19935668
references.citation: J Clin Invest. 1999 Nov;104(10):1363-74
references.pmid: 10562298
references.citation: J Cell Biol. 2007 Mar 12;176(6):877-88
references.pmid: 17353363
references.citation: J Biol Chem. 2007 Jun 29;282(26):18980-90
references.pmid: 17420255
references.citation: Calcif Tissue Int. 1985 May;37(3):287-92
references.pmid: 3926278
references.citation: J Cell Sci. 2005 Jul 1;118(Pt 13):2901-11
references.pmid: 15976449
references.citation: J Bone Miner Res. 2000 Aug;15(8):1477-88
references.pmid: 10934646
references.citation: Semin Cell Dev Biol. 2010 Oct;21(8):823-30
references.pmid: 20688183
references.citation: J Cell Biol. 2004 Feb 16;164(4):557-66
references.pmid: 14970193
references.citation: J Cell Biochem. 2003 May 1;89(1):165-79
references.pmid: 12682917
references.citation: Nature. 1993 Aug 19;364(6439):717-21
references.pmid: 8355785
references.citation: Mol Biol Cell. 2009 Sep;20(18):4021-30
references.pmid: 19641021
references.citation: Biochim Biophys Acta. 2000 Oct 31;1488(1-2):102-23
references.pmid: 11080681
references.citation: Mol Biol Cell. 2010 Dec;21(23):4162-72
references.pmid: 20943950
references.citation: Nat Neurosci. 2006 Jan;9(1):50-7
references.pmid: 16369480
references.citation: Cell. 2008 Feb 8;132(3):474-86
references.pmid: 18267077
references.citation: J Biol Chem. 2007 Jan 5;282(1):39-48
references.pmid: 17092936
references.citation: Nature. 1997 Jan 2;385(6611):89-93
references.pmid: 8985254
references.citation: J Cell Biol. 2007 Feb 26;176(5):641-51
references.pmid: 17325206
references.citation: J Cell Sci. 1995 Aug;108 ( Pt 8):2729-32
references.pmid: 7593313
references.citation: Nat Rev Genet. 2003 Aug;4(8):638-49
references.pmid: 12897775
references.citation: J Clin Invest. 2008 Jun;118(6):2088-97
references.pmid: 18464930
references.citation: Exp Cell Res. 2003 May 1;285(2):221-35
references.pmid: 12706117
references.citation: J Bone Miner Res. 2004 Feb;19(2):183-9
references.pmid: 14969387
references.citation: J Biol Chem. 2002 Oct 25;277(43):41147-56
references.pmid: 12171919
references.citation: J Biol Chem. 2001 Oct 19;276(42):39295-302
references.pmid: 11514537
references.citation: J Cell Sci. 2000 Dec;113 Pt 23:4165-76
references.pmid: 11069762
references.citation: J Clin Invest. 2004 Jul;114(1):85-93
references.pmid: 15232615
references.citation: EMBO J. 1997 Dec 1;16(23):6977-84
references.pmid: 9384577
references.citation: J Bone Miner Res. 1997 Jun;12(6):869-79
references.pmid: 9169344
references.citation: Nature. 1994 Jul 21;370(6486):216-8
references.pmid: 8028668