PML-1 protein ubiquitinates TAB1/TAK1 for LRP1 anti-inflammation signal

Promyelocytic leukaemia (PML) protein is multifunctional protein involved in numerous important cellular processes, such as tumour suppression, transcriptional regulation, apoptosis, DNA damage response, and viral defence ^1–3 . Recent studies have also shown that the PML protein plays a crucial role in regulating immune responses and inflammation ^4–6 . However, the precise mechanism by which it acts remains unclear. PML protein has the characteristic structural features of RBCC (RING, B-box, coiled-coil) and belongs to the single-ring E3 ubiquitin ligase family ^12–16 . Nevertheless, to date, no PML protein have been reported to exhibit ubiquitin ligase activity. Here, we show that PML protein can mediate the anti-inflammatory pathway of lipoprotein receptor-related protein 1 (LRP1) by inhibiting the protein TAB1/TAK1 in the Toll like receptor (TLR) pathway in vitro and in vivo. The PML-1 isoform mediating this pathway and the inhibitory effect of PML-1 on TAB1/TAK1 occurred via ubiquitin modification. These findings confirm that the PML-1 protein has E3 ubiquitin ligase activity and mediates the LRP1-PML-1-TAB1/TAK1 anti-inflammatory pathway. The newly discovered ubiquitin ligase function of the PML protein represents a major breakthrough in elucidating its multiple cellular functional mechanisms, and provides a novel strategy for developing anti-inflammatory immunotherapies targeting the human PML-1 protein.