Activation of MMP-9 activity by acrolein in saliva from patients with primary Sjogren's syndrome and its mechanism

作者：Uemura Takeshi; Suzuki Takehiro; Saiki Ryotaro; Dohmae Naoshi; Ito Satoshi; Takahashi Hoyu; Toida Toshihiko; Kashiwagi Keiko; Igarashi Kazuei^*

来源：International Journal of Biochemistry & Cell Biology, 2017, 88: 84-91.

DOI：10.1016/j.biocel.2017.05.004

• Acrolein conjugation
• Activation of 92 kDa MMP-9 (matrix metalloproteinase-9)
• Cysteine switch
• Propeptide domain
• Primary Sjogren's syndrome

We have recently reported that the altered recognition patterns of immunoglobulins due to acrolein conjugation are at least partially responsible for autoimmune diseases in patients with primary Sjogren's syndrome (pSS). In the current study, it was found that the specific activity (activity/rig protein) of metalloproteinase-9 (MMP-9) in saliva was elevated about 2.4-fold in pSS patients. Accordingly, it was examined whether MMP-9 is activated by acrolein. It was found that the MMP-9 with 92 kDa molecular weight was activated by acrolein. Under the conditions studied, Cys99, located in the propeptide, was conjugated with acrolein together with Cys230, 244, 302, 314, 329, 347, 361, 373, 388 and 516, which are located in fibronectin repeats and glycosyl domains, but not on the active site of MMP-9. In addition, 82 and 68 kDa constructs of MMP-9s, lacking the NH2-terminal domain that contains Cys99, were not activated by acrolein. The results suggest that acrolein conjugation at Cys99 caused the active site of MMP-9 to be exposed. Activation of MMP-9 by acrolein was inhibited by cysteine, and slightly by lysine, because these amino acids inhibited acrolein conjugation with MMP-9. Conversely, MMP9 activity in the presence of 50 mu M acrolein was enhanced by 100 mu M histidine. This was due to the inhibition of acrolein conjugation with His405 and 411 located at the Zn2+ binding site of MMP-9. These results suggest that activation of 92 kDa MMP-9 by acrolein is involved in tissue damage in pSS patients and is regulated by cysteine and histidine, and slightly by lysine. Activated 82 and 68 kDa MMP-9 s were not detected in saliva of pSS patients by Western blotting.

• 出版日期2017-7
• 单位RIKEN