Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner.

BACKGROUND: Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor. METHODS: In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method. RESULTS: We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells. CONCLUSIONS: In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.

The Roles of Host 5-Methylcytosine RNA Methyltransferases during Viral Infections.

Eukaryotic 5-methylcytosine RNA methyltransferases catalyze the transfer of a methyl group to the fifth carbon of a cytosine base in RNA sequences to produce 5-methylcytosine (m5C). m5C RNA methyltransferases play a crucial role in the maintenance of functionality and stability of RNA. Viruses have developed a number of strategies to suppress host innate immunity and ensure efficient transcription and translation for the replication of new virions. One such viral strategy is to use host m5C RNA methyltransferases to modify viral RNA and thus to affect antiviral host responses. Here, we summarize the latest findings concerning the roles of m5C RNA methyltransferases, namely, NOL1/NOP2/SUN domain (NSUN) proteins and DNA methyltransferase 2/tRNA methyltransferase 1 (DNMT2/TRDMT1) during viral infections. Moreover, the use of m5C RNA methyltransferase inhibitors as an antiviral therapy is discussed.