Dataset Information

O-GlcNAcylation stabilizes ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection

ABSTRACT: Human papillomaviruses (HPVs) are conducive to a fraction of head and neck squamous cell carcinoma (HNSCC). Previously we demonstrated that HPV16 oncogene E6 or E6/E7 transduction increases the abundance of O-linked GlcNAcylation (O-GlcNAc) transferase (OGT). Herein we focus on the effects of O-GlcNAcylation on HPV-positive HNSCCs. We found that upon HPV infection, ULK1, an autophagy-initiating kinase, is hyper-O-GlcNAcylated, stabilized and linked with autophagy elevation. Through mass spectrometry, we identified that ULK1 is O-GlcNAcylated at Ser409Ser410, which is distinct from previously reported Thr635Thr754. It has been known that PKCαmediates phosphorylation of ULK1 at Ser423, which attenuates its stability by shunting ULK1 to the chaperon-mediated autophagy (CMA) pathway. By biochemical assays, we demonstrate that ULK1 Ser409Ser410 O-GlcNAcylation antagonizes its phosphorylation at pSer423. Mutations of Ser409ASer410A (2A) render ULK1 less stable by promoting interaction with the CMA chaperon Hsc70. Moreover, ULK1-2A mutants attenuate the association of ULK1 with STX17, which is vital for the fusion between autophagosomes and lysosomes. Analysis of the TCGA database reveals that ULK1 is upregulated in HPV-positive HNSCCs and its protein level positively correlates with HNSCC patient survival. Our work demonstrates that O-GlcNAcylation of ULK1 alters to reciprocate to the environmental changes. O-GlcNAcylation of ULK1 at Ser409Ser410 stabilizes ULK1, and it might underlie the molecular mechanism of HPV-positive HNSCC patient survival.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ke Qin

LAB HEAD: Jing Li

PROVIDER: PXD031095 | Pride | 2022-10-14

REPOSITORIES: Pride

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O-GlcNAcylation stabilizes the autophagy-initiating kinase ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection.

Shi Yingxin Y Yan Sheng S Shao Guang-Can GC Wang Jinglong J Jian Yong-Ping YP Liu Bo B Yuan Yanqiu Y Qin Ke K Nai Shanshan S Huang Xiahe X Wang Yingchun Y Chen Zhenghui Z Chen Xing X Dong Meng-Qiu MQ Geng Yiqun Y Xu Zhi-Xiang ZX Li Jing J

The Journal of biological chemistry 20220803 9

Human papillomaviruses (HPVs) cause a subset of head and neck squamous cell carcinomas (HNSCCs). Previously, we demonstrated that HPV16 oncogene E6 or E6/E7 transduction increases the abundance of O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT), but OGT substrates affected by this increase are unclear. Here, we focus on the effects of O-GlcNAcylation on HPV-positive HNSCCs. We found that upon HPV infection, Unc-51-like kinase 1 (ULK1), an autophagy-initiating kinase, is hyper-O-GlcNA ...[more]

PMID: 35931119

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Project description:Introduction: Human Papilloma Virus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC), between 15% and 35% of HNSCC harboring HPV, almost exclusively of subtype 16. Demographic and exposure differences between HPV-positive (+) and negative (-) HNSCCs suggest that HPV(+) tumors may constitute a subclass with different biology, while clinical differences have also been observed. In this study, gene expression profiles of HPV(+) and (-) tumors were compared to further explore the biological effect of HPV in HNSCC. Methods: Thirty-six HNSCC tumors were analyzed for gene expression using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV using consensus primers for HPV L1, E6 and E7 by PCR and RT-PCR. Results: Eight (22%) of 36 tumors were positive for HPV, all of the HPV 16 subtype, and the HPV positive samples also expressed viral HPV E6 mRNA determined by RT-PCR. Patients with HPV(+) HNSCCs were on average younger than those with HPV(-) tumors (mean age 50.2 vs. 58.7). Statistical analysis using Significance Analysis of Microarrays (SAM) based on HPV status as a supervising parameter resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a sub-set of these genes were verified by RT-PCR. Genes highly expressed in HPV(+) samples included cell cycle regulators (p16INK4A, p18 and CDK2) and transcription factors (TAF7L, RFC4, RPA2 and TFDP2). The microarray data were also investigated using DIGMap to map genes by chromosomal location. A large number of genes on chromosome 3q24-qter was found to be overrepresented in HPV(+) tumors. Conclusion: The gene expression profile associated with HPV reflects alterations in cell cycle and proliferation signals. Further investigation of differentially expressed genes may reveal the unique pathways in HPV(+) tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment. Keywords: HPV, HNSCC, head and neck cancer, human, human papilloma virus

Dataset Information

O-GlcNAcylation stabilizes ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection

Publications

O-GlcNAcylation stabilizes the autophagy-initiating kinase ULK1 by inhibiting chaperone-mediated autophagy upon HPV infection.

Similar Datasets

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