Nuclear And Cytoplasmic Pathways Contribute Differentially To The Catabolism Of Normal And Mutant Blimp-1s In B Cell Lymphoma

Blimp1(B lymphocyte induced maturation protein 1)also named PRDM1(Positive Regulatory Domain zinc finger protein 1),it is a very important transcription factor.A proper expression of Blimp-1 is required for B cells' maturation into plasma cells,and the instability of Blimp-1 underlies the development of certain B-cell lymphomas.However,how Blimp-1 is catabolized remains largely unclear.2011 Shimshon first reported that Blimp1 could be modifed by SUMO-1,then be degraded by proteasome,and SENP1 could raise Blimp1 protein level.However,2012 Ying found PIAS1 could promote SUMO1 ylation of Blimp1,and that had a crucial role in plasma cell differentiation,but this modification did not affect the stability of Blimp1.2014 Yang revealed that Hrd1 could promot ubiquitination of Blimp1,then be degradated by proteasome.The SUMOylation is happened in nuclear,whereas the ubiquitination is in cytoplasma,the relationship between the two pathways is unclear.Here we show that the PR domain-misfolding mutation I107 R or P84 R,as identified in two lymphoma cases,compromises Blimp-1 function by sensitizing it to proteasome-mediated degradation.Mechanistically,Blimp-1 mutants' half-lives are largely shortened by an Hrd1-mediated cytoplasmic sequestering and subsequent degradation wherein HSP70 play opposite regulatory roles.Nevertheless,once transferring into nucleus the minor portion of mutant Blimp-1s are subject to a polymeric sumoylation-and PML nuclear body-dependent degradation pathway as normal Blimp-1 does.Furthermore,we show that specific interference of Hrd1/mutant Blimp-1 association significantly stabilizes mutant Blimp-1s and restore their nuclear localization,resulting in differentiation and/or apoptosis of lymphoma cells.Collectively,these results yield insights into a possible Hrd-1-targeting strategy for the treatment of lymphoma.