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

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.

E3 ubiquitin ligase ASB17 is required for spermiation in mice

“…In line with previous findings (24), Asb17-KO mice were viable, and fertility tests revealed normal fertility in Asb17-KO adult males, compared with WT or heterozygous (+/−) mice (Figure 2A). The testes weight was comparable between Asb17-KO and WT mice (Figure 2B,2C).…”

“…In addition to the known roles of ASB17 in promoting spermatogenic cell apoptosis (24), in the present study, we uncovered a novel mechanism in spermiation involving ASB17-mediated ubiquitination and degradation of the ES associated protein, ESPN. Consistent with the previous work (24), we found that Asb17-KO males were fertile and showed complete spermatogenesis. However, we also showed that Asb17-KO males exhibited oligozoospermia, which was considered to be a major result of spermiation failure found in Asb17-KO.…”

“…However, ASB17 deficiency leads to a significant reduction of apoptosis in germ cells and prevents spermatogonial apoptosis as induced by etoposide in vivo. Mechanistically, the authors found that ASB17 mediated the ubiquitylation and degradation of two anti-apoptotic factors, BCLW and MCL1 in vitro (24). Taken together, the above data suggests that ASB17 plays a minor but not crucial role during spermatogenesis.…”

“…Expression profiling of ASB17 in 16 human tissues and 14 mouse tissues by Northern blot has shown that ASB17 is expressed exclusively in the testis, suggesting a potential role of ASB17 in spermatogenesis (22,23). Recently, using a gene KO approach, Yang et al, have shown that ASB17deficient mice undergo normal testicular development and fertility (24). However, ASB17 deficiency leads to a significant reduction of apoptosis in germ cells and prevents spermatogonial apoptosis as induced by etoposide in vivo.…”

Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy

“…It should be noted that the delicate balance between anti-and proapoptotic proteins of the Bcl-2 family determines the life and death decisions of cells. This balance is influenced by several factors, including interaction, localization, expression level, half-life, and PTM of Bcl-2 proteins [83,[216][217][218][219][220]. During different stages of tumorigenesis and metastasis, cancer cells evade apoptosis by modulating Bcl-2 protein family members, such as by the upregulation of antiapoptotic Bcl-2 proteins and the downregulation or removal of proapoptotic Bcl-2 members [221].…”