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Anti-inflammatory activity of SMP30 modulates NF-κB through protein tyrosine kinase/phosphatase balance

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Abstract

Recent studies on senescence marker protein-30 (SMP30) have shown that it has an important functional role in the aging process, but its precise participation in cellular works has not been fully determined. We hypothesize that SMP30 plays crucial roles in signaling processes by modulating the balance of protein tyrosine kinase (PTK)/protein tyrosine phosphatase (PTP) and in activating proinflammatory NF-κB. An experimental paradigm of gain and loss of SMP30 function was established using SMP30-overexpressed YPEN-1 cells (herein referred to as “SMP30(+) cells”) and SMP30Y/− knockout mouse kidneys. The resulting data show that SMP30 expression suppressed oxidative stress-induced PTK/PTP dysregulation and PP1/2A inactivation in SMP30(+) cells, leading to the suppression of NF-κB activation. In the kidneys of SMP30Y/− mice, SMP30 deficiency was found to induce NF-κB activation via the upstream signaling of NIK/IKK and MAPKs and to upregulate downstream NF-κB-responsive gene expression. In this study, we also demonstrate for the first time that SMP30 deficiency induced PTK activity in SMP30Y/− kidneys, thereby significantly increasing the tyrosine phosphorylation of a catalytic subunit of PP2A (PP2Ac-Tyr307). Based on these findings, we propose that SMP30 involves NF-κB regulation through the PTK/PTP balance and that the age-related decrease of SMP30 causes NF-κB activation, which contributes to an exacerbation of the inflammatory process during aging.

Key messages

  • SMP30-deficient mice induced a shorter lifespan and redox changes.

  • Overexpression of SMP30 prevented oxidative stress insults.

  • The depletion of SMP30 increased redox-related PTK/PTP imbalance and PP1/PP2A inactivation.

  • The depletion of SMP30 caused an elevation of NF-κB-responsive inflammatory markers.

  • SMP30 may be a potent inhibitory protein against oxidative stress and chronic inflammation.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No.2009-0083538).

We thank the Aging Tissue Bank for providing research materials for this study.

Conflict of interest

The authors have no conflict of interest to disclose.

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Authors and Affiliations

  1. Korea Institute of Toxicology, 141 Gajungro, Yuseong-gu, Daejeon, 305-343, Republic of Korea

    Kyung ** Jung, Su ** Kim & Chang Woo Song

  2. Department of Human and Environmental Toxicology, Korea University of Science and Technology, 217 Gajungro, Yuseong-gu, Daejeon, 305-333, Republic of Korea

    Kyung ** Jung, Su ** Kim & Chang Woo Song

  3. Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea

    Eun Kyeong Lee, Nam Deuk Kim, Dong-Soon Im, Byung Pal Yu & Hae Young Chung

  4. Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan

    Naoki Maruyama & Akihito Ishigami

  5. Department of Physiology, University of Texas Health Science Center, San Antonio, TX, 78229, USA

    Byung Pal Yu

  6. Department of Pharmacy, College of Pharmacy, Pusan NationalUniversity, Gumjung-gu, Busan, 609-735, Republic of Korea

    Kyung ** Jung, Eun Kyeong Lee, Nam Deuk Kim, Dong-Soon Im & Hae Young Chung

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  1. Kyung ** Jung
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Correspondence to Hae Young Chung.

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Jung, K.J., Lee, E.K., Kim, S.J. et al. Anti-inflammatory activity of SMP30 modulates NF-κB through protein tyrosine kinase/phosphatase balance. J Mol Med 93, 343–356 (2015). https://doi.org/10.1007/s00109-014-1219-1

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  • DOI: https://doi.org/10.1007/s00109-014-1219-1

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