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Functional cleavage of selenoprotein K is regulated by calpain/calpastation system in toll‐like receptor activated macrophages
Author(s) -
HUANG ZHI,
Hoffmann FuKun W.,
Hashimoto Ann S.,
Hoffmann Peter R.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.823.25
Subject(s) - cleavage (geology) , immune system , selenoprotein , biochemistry , chemistry , biology , enzyme , microbiology and biotechnology , immunology , paleontology , glutathione , glutathione peroxidase , fracture (geology)
Calpains (CAPN) are proteolytic enzymes that modulate cellular function through cleavage of targets. Calpastatin (CAST) is a key endogenous inhibitor of CAPN, thereby modifying its actions. An important role is emerging for CAPN/CAST system in regulating immune responses. Herein, we identify a novel target of CAPN, selenoprotein K (SelK), which is important for Ca 2+ flux in immune cells. CAPN‐mediated cleavage of SelK was detected in myeloid cells but not in lymphoid cells. Both m‐ and μ‐CAPN were capable of cleaving SelK, but m‐CAPN was the predominant isoform. Specific inhibitors of CAPN were used to show that m‐CAPN cleaved SelK in macrophages. The cleavage site in SelK was identified between Arg81 and Gly82 and the resulting truncated SelK was shown to lack selenocysteine, the amino acid that defines selenoproteins. Resting macrophages predominantly expressed cleaved SelK and, when activated through Toll‐like receptors (TLRs), SelK cleavage was inhibited. We found that decreased CAPN cleavage was due to TLR‐induced up‐regulation of CAST. CAST knock down resulted in higher CAPN activity and sustained SelK cleavage in TLR activated macrophage. Moreover, the expression of the CAPN and CAST in macrophages was different from T and B cells. Overall, our findings identify SelK as a novel CAPN target and reveal dynamic changes in functional cleavage of SelK is regulated by CAPN/CAST system in TLR activated macrophages.