Journal
JOURNAL OF MOLECULAR MEDICINE-JMM
Volume 95, Issue 3, Pages 273-285Publisher
SPRINGER
DOI: 10.1007/s00109-016-1479-z
Keywords
TIMAP; TGF beta; HDAC3; MLC phosphorylation; Macrophage polarization; Phagocytosis
Funding
- National Nature Science Foundation of China [81271301, 81470940, 81670672]
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TIMAP (TGF beta-inhibited membrane-associated protein) is an endothelium-enriched TGF beta downstream protein and structurally belongs to the targeting subunit of myosin phosphatase; however, the mechanism of TGF beta repressing TIMAP and its functional relevance to TGF beta bioactivity remain largely unknown. Here, we report that TIMAP is reduced in TGF beta-elevated mouse fibrotic kidney and highly expressed in macrophages. TGF beta repression of TIMAP is associated with HDAC3 upregulation and its recruitment by Smad2/3 at the Smad binding element on TIMAP promoter, whereas specific HDAC3 inhibition reversed the TIMAP repression, suggesting that TGF beta transcriptionally downregulates TIMAP through HDAC3-associated Smad signaling. Further investigation showed that TIMAP over-expression interrupted TGF beta-associated Smad signaling and TIMAP repression by TGF beta correlated with TGF beta-induced macrophage M2 polarization markers, migration, and phagocytosis-the processes promoted by phosphorylation of the putative TIMAP substrate myosin light chain (MLC). Consistently, TIMAP dephosphorylated MLC in macrophages and TGF beta induced macrophage migration and phagocytosis in TIMAP-and MLC phosphorylation-dependent manners, suggesting that TIMAP dephosphorylation of MLC constitutes an essential regulatory loop mitigating TGF beta-associated macrophage M2 phenotypic activities. Given that hyperactive TGF beta often causes excessive macrophage phagocytic activities potentially leading to various chronic disorders, the strategies targeting HDAC3/TIMAP axis might improve TGF beta-associated pathological processes.
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