The Biological Function Of RNF31 In The Regulation Of Hematopoiesis,Inflammation And Tumorigenesis

To date,the linear ubiquitin chain assembly complex（LUBAC）is the only known E3ligase complex that could generate linear ubiquitin chains on different substrates.LUBAC is widely involved in the process of embryo,inflammation,immune signaling and cell death.Recent studies suggest that HOIL-1,the subunit of LUBAC,could mediated the development of hematopoiesis,but the molecular mechanism still remians unclear.And RNF31 working as the catalytic subunit of LUBAC,we next sought to explore the possibility that RNF31 regulates the homeostasis of hematopoiesis,which will further elucidate the more physiological function of linear ubiquitination.Here,we generated Rnf31^fl/flVav-Cre mice in which specifically blocked RNF31 inhematopoietic lineage and found RNF31 is vital for positive regulation of hematopoiesis.For the molecular mechanism,RNF31 defeciency in HSPCs could greatly enhanced TNF-induced cell death but attenuated MAPK signaling activation.Ablation of TNFin Rnf31^fl/flVav-Cre mice could enable the development of hematopoiesis at embryonic stage,In the same time,depletion of MLKL and Caspase8 prevents the postnatal bone marrow failure in Rnf31^fl/flVav-Cre mice.We found cell death is responsible for the postnatal bone marrow failure in Rnf31^fl/flVav-Cre mice.Of note,abnormal hematopoietic transcriptional factors and enhanced JAK-STAT activation are responsible for the spontaneous inflammation in Rnf31^fl/flVav-Cre Mlkl^-/-Caspase8^-/-adult mice.And we found RNF31 maintains the development and homeostasis of the hematopoietic system in mice during adulthood by regulating the expression level of hematopoietic transcription factors.In addition,we comprehensively explored the role of RNF31 in regulatingtumorigenesis and tumor micro-environment.And we found RNF31 in macrophages and dendritic cells is dispensable for tumorigenesis and antitumor immunity.However,RNF31 in tumor cell is critical for tumorigenesis.Mechanistically,RNF31 is dispensable for the proliferation of B16 melanoma cells.Deleting of RNF31 in melanoma cell show better tumor control with increasing intratumoral CD8⁺T cells infilitration and killing via promoting TNF/IFNγ-induced RIPK1 kinase activation and apoptosis.Collectively,our results uncover the physiological biology and molecular mechanism of RNF31 mediated linear ubiquitination on hematopoiesis and tumorigenesis will be of great benefit for designing new therapeutic approaches in related human diseases.