OTUD1 Activates Caspase‐Independent and Caspase‐Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation

Abstract

Apoptosis‐inducing factor (AIF) plays a dual role in regulating cell survival and apoptosis, acting as a prosurvival factor in mitochondria via its NADH oxidoreductase activity and activating the caspase‐independent apoptotic pathway (i.e., parthanatos) after nuclear translocation. However, whether one factor conjunctively controls the separated functions of AIF is not clear. Here, it is shown that OTU deubiquitinase 1 (OTUD1) acts as a link between the two functions of AIF via deubiquitination events. Deubiquitination of AIF at K244 disrupts the normal mitochondrial structure and compromises oxidative phosphorylation, and deubiquitination of AIF at K255 enhances its DNA‐binding ability to promote parthanatos. Moreover, OTUD1 stabilizes DDB1 and CUL4 associated factor 10 (DCAF10) and recruits the cullin 4A (CUL4A)‐damage specific DNA binding protein 1 (DDB1) complex to promote myeloid cell leukemia sequence 1 (MCL1) degradation, thereby activating caspase‐dependent apoptotic signaling. Collectively, these results reveal the central role of OTUD1 in activating both caspase‐independent and caspase‐dependent apoptotic signaling and propose decreased OTUD1 expression as a key event promoting chemoresistance in esophageal squamous cell carcinoma.

Melatonin induces apoptotic cell death through Bim stabilization by Sp1‐mediated OTUD1 upregulation

“…OTUD1 induced apoptotic cancer cell death through p53 stabilization 10 . Recently, Luo et al reported that OTUD1 induced stabilization of DCAF10 and recruited the cullin 4A damage‐specific DNA binding protein 1 (DDB1) to promote Mcl‐1 ubiquitination 33 …”

OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

“…Whereas, in Otud1 -/--MEFs, increased intranuclear AIFM1 was detected concomitantly with the reduced mitochondrial AIFM1 (Extended Data Fig. 5c), which may affect mitochondrial oxidative phosphorylation and ROS generation 20 . These results indicated that OTUD1 physiologically binds and regulates the K63-ubiquitylation of KEAP1 under basal conditions and is important for the efficient antioxidative stress response, ROS production, and oxeiptosis.…”

“…In this study, we examined the effects of 88 human DUBs on LUBAC-mediated NF-κB activation, and identified an OTU-family DUB, OTUD1 (also known as DUBA7) 17 , as the most potent down-regulator. OTUD1 reportedly regulates tumour progression 18 , cell death 19,20 , innate immune responses [21][22][23] , YAP signalling 24 , autoimmune disease 25 , iron transport 26 , and inhibition of colonic inflammation 27 , whereas the regulatory mechanism of OTUD1 on the NF-κB pathway has not been revealed.…”

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention

“…However, xanthohumol downregulated HK2 and glycolysis and subsequently increased cytochrome c release to activate the intrinsic (mitochondrial) apoptotic pathway in the HT29, SW480, LOVO, HCT116, and SW620 colorectal cancer cell lines [13]. The apoptosis-inducing factor (AIF), a mitochondrial protein, is implicated in caspase-independent programmed cell death following its translocation to the nucleus [110]. In an in vitro investigation using multiple biochemical assays, xanthohumol was detected to cause proliferation inhibition and death of the rat glioma C6 cells (in a time-and dose-dependent manner) via a mechanism of inducing AIF pathway apoptosis by triggering mitochondrial stress [111].…”