SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1.

SIRT2, a cytoplasmic member of the Sirtuin family, has important roles in immunity and inflammation. However, its function in regulating the response to DNA virus infection remains elusive. Here, we find that SIRT2 is a unique regulator among the Sirtuin family that negatively modulates the cGAS-STING-signaling pathway. SIRT2 is down-regulated after Herpes simplex virus-1 (HSV-1) infection, and SIRT2 deficiency markedly elevates the expression levels of type I interferon (IFN). SIRT2 inhibits the DNA binding ability and droplet formation of cGAS by interacting with and deacetylating G3BP1 at K257, K276, and K376, leading to the disassembly of the cGAS-G3BP1 complex, which is critical for cGAS activation. Administration of AGK2, a selective SIRT2 inhibitor, protects mice from HSV-1 infection and increases the expression of IFN and IFN-stimulated genes. Our study shows that SIRT2 negatively regulates cGAS activation through G3BP1 deacetylation, suggesting a potential antiviral strategy by modulating SIRT2 activity.

SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis.

Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the role of SLC25A51 in human disease, such as cancer, remains undefined. Here, we report that SLC25A51 is upregulated in multiple cancers, which promotes cancer cells proliferation. Loss of SLC25A51 elevates the mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, leading to the impairment of P5CS enzymatic activity, which is the key enzyme in proline biogenesis, and the reduction in proline contents. Notably, we find fludarabine phosphate, an FDA-approved drug, is able to bind with and inhibit SLC25A51 functions, causing mitochondrial NAD+ decrease and proteins hyperacetylation, which could further synergize with aspirin to reinforce the anti-tumor efficacy. Our study reveals that SLC25A51 is an attractive anti-cancer target, and provides a novel drug combination of fludarabine phosphate with aspirin as a potential cancer therapy strategy.

The phosphorylation of PHF5A by TrkA-ERK1/2-ABL1 cascade regulates centrosome separation.

During interphase, the newly duplicated pairs of centrosomes are held together by a centrosome linker, and the centrosome separation needs the disruption of this linker to induce the duplicated centrosomes separating into two distinct microtubule organization centers. The mechanism of regulating centrosome separation is however poorly understood. Here, we demonstrated that the phosphorylation of PHF5A at Y36 by the TrkA-ERK1/2-ABL1 cascade plays a critical role in regulating centrosome separation. PHF5A, a well-characterized spliceosome component, is enriched in the centrosome. The pY36-PHF5A promotes the interaction between CEP250 and Nek2A in a spliceosomal-independent manner, which leads to premature centrosome separation. Furthermore, the unmatured centrosome remodels the microtubule and subsequently regulates cell proliferation and migration. Importantly, we found that the phosphorylation cascade of TrkA-ERK1/2-ABL1-PHF5A is hyper-regulated in medulloblastoma. The inhibition of this cascade can induce senescence and restrict the proliferation of medulloblastoma. Our findings on this phosphorylation cascade in regulating centrosome separation could provide a series of potential targets for restricting the progress of medulloblastoma.

Acetylation dependent translocation of EWSR1 regulates CHK2 alternative splicing in response to DNA damage.

Ewing sarcoma breakpoint region 1 (EWSR1) is a member of FET (FUS/EWSR1/TAF15) RNA-binding family of proteins. The Ewing sarcoma oncoprotein EWS-FLI1 has been extensively studied, while much less is known about EWSR1 itself, especially the potential role of EWSR1 in response to DNA damage. Here, we found that UV irradiation induces acetylation of EWSR1, which is required for its nucleoli translocation. We identified K423, K432, K438, K640, and K643 as the major acetylation sites, p300/CBP and HDAC3/HDAC10 as the major acetyltransferases and deacetylases, respectively. Mechanically, UV-induced EWSR1 acetylation repressed its interaction with spliceosomal component U1C, which caused abnormal splicing of CHK2, suppressing the activity of CHK2 in response to UV irradiation. Taken together, our findings uncover acetylation as a novel regulatory modification of EWSR1, and is essential for its function in DNA damage response.

Exosomal microRNAs induce tumor-associated macrophages via PPARγ during tumor progression in SHH medulloblastoma.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is composed of at least four molecular subgroups with distinct clinical characteristics. The sonic hedgehog (SHH) subgroup exhibits the most abundant tumor-associated microglia/macrophages (TAMs) infiltration. SHH-MB patients treated by anti-SHH drugs showed high drug resistance. However, the comprehensive role of TAMs in SHH-MB remains enigma. The aim of this study is to explore the mechanism of TAM activation/polarization in SHH-MB and discover a potential immunotherapeutic target to reduce drug resistance. We first analyzed expression profiles of immuno-microenvironment (IME) in four subgroups of 48 MB tumors using NanoString PanCancer IO360 panel and found TAMs were the major component of IME in SHH-MBs. We further distinguished M1/M2-like TAMs in tumors and found M2-like macrophages, rather than microglia, were enriched in SHH-MBs. In transgenic SHH-MB mice, these TAMs had close relationship with tumor progression. Polarization of the TAMs could be induced by MB-derived exosomes in vitro. We then screened SHH MB-derived exosomal miRNAs and their target genes using RNA sequencing and luciferase assay to clarify their roles in regulating TAM polarization. We found down-regulated let-7i-5p and miR-221-3p can induce M2-like polarization of TAMs via upregulating peroxisome proliferator activated receptor gamma (PPARγ). Finally, we demonstrated the PPARγ antagonist efficiently improved the antitumor activity of SMO inhibitor in vivo, which may be related to inhibition of M2-like TAMs. Our findings suggest a potential therapeutic strategy for SHH-MB by targeting tumor-supportive M2-like TAMs to enhance the therapeutic effect of SMO inhibitors.

PYCR, a key enzyme in proline metabolism, functions in tumorigenesis.

Pyrroline-5-carboxylate reductase (PYCR), the last enzyme in proline synthesis that converts P5C into proline, was found promoting cancer growth and inhibiting apoptosis through multiple approaches, including regulating cell cycle and redox homeostasis, and promoting growth signaling pathways. Proline is abnormally up-regulated in multiple cancers and becomes one of the critical players in the reprogramming of cancer metabolism. As the last key enzymes in proline generation, PYCRs have been the subject of many investigations, and have been demonstrated to play an indispensable role in promoting tumorigenesis and cancer progression. In this article, we will thoroughly review the recent investigations on PYCRs in cancer development.

Citrate synthase desuccinylation by SIRT5 promotes colon cancer cell proliferation and migration.

Citrate synthase (CS), the rate-limiting enzyme in the tricarboxylic acid (TCA) cycle catalyzes the first step of the cycle, namely, the condensation of oxaloacetate and acetyl-CoA to produce citrate. The expression and enzymatic activity of CS are altered in cancers, but posttranslational modification (PTM) of CS and its regulation in tumorigenesis remain largely obscure. SIRT5 belongs to the nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase sirtuin family and plays vital roles in multiple biological processes via modulating various substrates. Here, we show that SIRT5 interacts with CS and that SIRT5 desuccinylates CS at the evolutionarily conserved residues K393 and K395. Moreover, hypersuccinylation of CS at K393 and K395 dramatically reduces its enzymatic activity and suppresses colon cancer cell proliferation and migration. These results provide experimental evidence in support of a potential therapeutic approach for colon cancer.