Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress

Ming Gao; Minjun Chen; Changying Li; Ming Xu; Yun Liu; Min Cong; Nan Sang; Sijin Liu

doi:10.1038/s41421-017-0005-y

Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress

Cell Discov. 2018 Jan 30:4:5. doi: 10.1038/s41421-017-0005-y. eCollection 2018.

Authors

Ming Gao^{1

2}, Minjun Chen^{1

3}, Changying Li^{1

4}, Ming Xu^{1

2}, Yun Liu^{1

5}, Min Cong⁴, Nan Sang³, Sijin Liu^{1

2}

Affiliations

¹ 1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085 China.
² 2University of Chinese Academy of Sciences, Beijing, 100049 China.
³ 3College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, Shanxi 030006 China.
⁴ 4Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050 China.
⁵ Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031 China.

Abstract

Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity in hepatocytes. There are various gene variants and pseudogenes for MTs; however, there is little understanding on the functions of those non-coding MT members that are known to be expressed as long non-coding RNAs (lncRNAs) nowadays. Different from most protein-coding MT members, MT1DP was here found that remarkably induced to provoke cytotoxicity in hepatocytes in response to Cd treatment. MT1DP exerted such a pro-apoptotic function in Cd-treated hepatocytes through interacting with two partners: RhoC and MT1H. On one hand, MT1DP interacted with RhoC protein to increase the latter's stability by preventing lysosome-dependent protein degradation. Therefore, upon Cd stress, MT1DP/RhoC complex was quickly reinforced to activate RhoC-CCN1/2-AKT signaling and potentiate Ca²⁺ influx, leading to enhanced Cd uptake and elevated Cd toxicity. On the other hand, MT1H, a protein-coding member of the MT family with little known function, was found to quickly respond to Cd exposure along with MT1DP. Mechanistically, MT1H and MT1DP were uncovered to mutually protect each other through a reciprocal ceRNA mechanism, building up a positive feedback loop to enforce MT1DP-conducted signaling upon Cd exposure. Moreover, MT1DP was found to contribute much more to the activation of RhoC-CCN1/2-AKT signaling than MT1H. Considered together, we here unveiled a mystery whether a pseudogene within the MT family, MT1DP, has actual biological functions in regulating Cd-induced cellular defense. Our findings unearthed an important role of pseudogene MT1DP in calibrating the cellular machinery to switch the cellular defense to cytotoxicity through crosslinking an interplay between its two partners, namely MT1H and RhoC, under cadmium stress.