RESUMO
SAP05, a secreted effector by the obligate parasitic bacteria phytoplasma, bridges host SPL and GATA transcription factors (TFs) to the 26 S proteasome subunit RPN10 for ubiquitination-independent degradation. Here, we report the crystal structures of SAP05 in complex with SPL5, GATA18 and RPN10, which provide detailed insights into the protein-protein interactions involving SAP05. SAP05 employs two opposing lobes with an acidic path and a hydrophobic path to contact TFs and RPN10, respectively. Our crystal structures, in conjunction with mutagenesis and degradation assays, reveal that SAP05 targets plant GATAs but not animal GATAs dependent on their direct salt-bridged electrostatic interactions. Additionally, SAP05 hijacks plant RPN10 but not animal RPN10 due to structural steric hindrance and the key hydrophobic interactions. This study provides valuable molecular-level information into the modulation of host proteins to prevent insect-borne diseases.
Assuntos
Fatores de Transcrição , Ubiquitina , Ubiquitina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , UbiquitinaçãoRESUMO
Invasive micropapillary carcinoma (IMPC) has very high rates of lymphovascular invasion and lymph node metastasis and has been reported in several organs. However, the genomic mechanisms underlying its metastasis are unclear. Here, we perform whole-genome sequencing of tumor cell clusters from primary IMPC and paired axillary lymph node metastases. Cell clusters in multiple lymph node foci arise from a single subclone of the primary tumor. We find evidence that the monoclonal metastatic ancestor in primary IMPC shares high frequency copy-number loss of PRDM16 and IGSF9 and the copy number gain of ALDH2. Immunohistochemistry analysis further shows that low expression of IGSF9 and PRDM16 and high expression of ALDH2 are associated with lymph node metastasis and poor survival of patients with IMPC. We expect these genomic and evolutionary profiles to contribute to the accurate diagnosis of IMPC.
Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Neoplasias da Mama/genética , Carcinoma Papilar/genética , Proteínas de Ligação a DNA/genética , Imunoglobulinas/genética , Metástase Linfática/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Papilar/metabolismo , Carcinoma Papilar/mortalidade , Carcinoma Papilar/patologia , Proteínas de Ligação a DNA/metabolismo , Evolução Molecular , Feminino , Dosagem de Genes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoglobulinas/metabolismo , Família Multigênica , Invasividade Neoplásica , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais , Análise de Sobrevida , Fatores de Transcrição/metabolismoRESUMO
Invasive micropapillary carcinoma (IMPC) is a special histological subtype of breast cancer, featured with extremely high rates of lymphovascular invasion and lymph node metastasis. Based on a previous series of studies, our team proposed the hypothesis of "clustered metastasis of IMPC tumor cells". However, the transcriptomics characteristics underlying its metastasis are unknown, especially in spatial transcriptomics (ST). In this paper, we perform ST sequencing on four freshly frozen IMPC samples. We draw the transcriptomic maps of IMPC for the first time and reveal its extensive heterogeneity, associated with metabolic reprogramming. We also find that IMPC subpopulations with abnormal metabolism are arranged in different spatial areas, and higher levels of lipid metabolism are observed in all IMPC hierarchical clusters. Moreover, we find that the stromal regions show varieties of gene expression programs, and this difference depends on their distance from IMPC regions. Furthermore, a total of seven IMPC hierarchical clusters of four samples share a common higher expression level of the SREBF1 gene. Immunohistochemistry results further show that high SREBF1 protein expression is associated with lymph node metastasis and poor survival in IMPC patients. Together, these findings provide a valuable resource for exploring the inter- and intra-tumoral heterogeneity of IMPC and identify a new marker, SREBF1, which may facilitate accurate diagnosis and treatment of this disease.
