E3 Ubiquitin Ligase ASB17 Promotes Apoptosis by Ubiquitylating and Degrading BCLW and MCL1

SIMPLE SUMMARY: B-cell lymphoma-2 family proteins have been widely accepted as the critical regulators in cell apoptosis, often found to be abnormally expressed in many cancers. Among them, B-cell leukemia/lymphoma w and myeloid cell leukemia-1 are two pro-survival proteins. Here, we reported that the ankyrin repeat and SOCS box protein 17 can degrade the two proteins in a ubiquitylation -dependent way. Furthermore, we generated the first ASB17 knockout C57BL/6J mice line. The results revealed that ASB17 deficiency inhibited apoptosis but did not affect testes development. Moreover, the ASB17-deficient mice were more resistant to the stimuli of etoposide, Altogether, these findings indicate that ASB17 is a novel positive mediator of cell apoptosis. ABSTRACT: Apoptosis is a very important process of cell death controlled by multiple genes during which cells undergo certain events before dying. Apoptosis helps to clean the unnecessary cells and has critical physiological significance. Altered apoptosis results in a disorder of cell death and is associated with many diseases such as neurodegenerative diseases and cancers. Here, we reported that the ankyrin repeat and SOCS box protein 17 (ASB17) was mainly expressed in the testis and promoted apoptosis both in vivo and in vitro. Analyzing ASB17-deficient mice generated by using the CRISPR/Cas9 system, we demonstrated that ASB17 deficiency resulted in the reduction of apoptosis in spermatogenic cells, but it did not affect the development of spermatozoa or normal fertility. Next, in an in vivo model, ASB17 deficiency prevented the apoptosis of spermatogonia induced by etoposide in male mice. We noted that ASB17 promoted apoptosis in a caspase-dependent manner in vitro. Moreover, ASB17 interacted with the members of the BCL2 family, including BCL2, BCLX, BCLW, and MCL1. Interestingly, ASB17 specifically degraded the two anti-apoptotic factors, BCLW and MCL1, in a ubiquitylation-dependent fashion. Collectively, our findings suggested that ASB17 acted as a distinct positive regulator of cell apoptosis.