Publications

• Identification of SIRT3 as an eraser of H4K16la.

  Fan Z., Liu Z., Zhang N., Wei W., Cheng K., Sun H., Hao Q.

  Lysine lactylation (Kla) is a novel histone post-translational modification discovered in late 2019. Later, HDAC1-3, were identified as the robust Kla erasers. While the Sirtuin family proteins showed weak eraser activities toward Kla, as reported. However, the catalytic mechanisms and physiologic ... >> More

  Lysine lactylation (Kla) is a novel histone post-translational modification discovered in late 2019. Later, HDAC1-3, were identified as the robust Kla erasers. While the Sirtuin family proteins showed weak eraser activities toward Kla, as reported. However, the catalytic mechanisms and physiological functions of HDACs and Sirtuins are not identical. In this study, we observed that SIRT3 exhibits a higher eraser activity against the H4K16la site than the other human Sirtuins. Crystal structures revealed the detailed binding mechanisms between lactyl-lysine peptides and SIRT3. Furthermore, a chemical probe, p-H4K16laAlk, was developed to capture potential Kla erasers from cell lysates. SIRT3 was captured by this probe and detected via proteomic analysis. And another chemical probe, p-H4K16la-NBD, was developed to detect the eraser-Kla delactylation processes directly via fluorescence indication. Our findings and chemical probes provide new directions for further investigating Kla and its roles in gene transcription regulation. << Less

  IScience 26:107757-107757(2023) [PubMed] [EuropePMC]

• SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth.

  Jin J., Bai L., Wang D., Ding W., Cao Z., Yan P., Li Y., Xi L., Wang Y., Zheng X., Wei H., Ding C., Wang Y.

  Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD⁺ -dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to ... >> More

  Lysine lactylation (Kla) is a recently discovered histone mark derived from metabolic lactate. The NAD⁺ -dependent deacetylase SIRT3, which can also catalyze removal of the lactyl moiety from lysine, is expressed at low levels in hepatocellular carcinoma (HCC) and has been suggested to be an HCC tumor suppressor. Here we report that SIRT3 can delactylate non-histone proteins and suppress HCC development. Using SILAC-based quantitative proteomics, we identify cyclin E2 (CCNE2) as one of the lactylated substrates of SIRT3 in HCC cells. Furthermore, our crystallographic study elucidates the mechanism of CCNE2 K348la delactylation by SIRT3. Our results further suggest that lactylated CCNE2 promotes HCC cell growth, while SIRT3 activation by Honokiol induces HCC cell apoptosis and prevents HCC outgrowth in vivo by regulating Kla levels of CCNE2. Together, our results establish a physiological function of SIRT3 as a delactylase that is important for suppressing HCC, and our structural data could be useful for the future design of activators. << Less

  EMBO Rep. 24:e56052-e56052(2023) [PubMed] [EuropePMC]

• The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.

  Ju J., Zhang H., Lin M., Yan Z., An L., Cao Z., Geng D., Yue J., Tang Y., Tian L., Chen F., Han Y., Wang W., Zhao S., Jiao S., Zhou Z.

  Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, l ... >> More

  Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation. << Less

  J. Clin. Invest. 134:0-0(2024) [PubMed] [EuropePMC]

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