Regulation of Early Wave of Germ Cell Apoptosis and Spermatogenesis by Deubiquitinating Enzyme CYLD

Abstract

Spermatogenesis involves an early wave of germ cell apoptosis, which is required for maintaining the balance between germ cells and supporting Sertoli cells. However, the signaling mechanism regulating this apoptotic event is poorly defined. Here we show that genetic deficiency of Cyld, a recently identified deubiquitinating enzyme, attenuates the early wave of germ cell apoptosis and causes impaired spermatogenesis in mice. Interestingly, the loss of CYLD in testicular cells leads to activation of the transcription factor NF-kappaB and aberrant expression of antiapoptotic genes. We further show that CYLD negatively regulates a ubiquitin-dependent NF-kappaB activator, RIP1. CYLD binds to RIP1 and inhibits its ubiquitination and signaling function. These findings establish CYLD as a pivotal deubiquitinating enzyme (DUB) that regulates germ cell apoptosis and spermatogenesis and suggest an essential role for CYLD in controlling the RIP1/NF-kappaB signaling axis in testis.

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6

“…We found that the flagella were much shorter or even absent in CYLD knockout sperm ( Figure 1A and 1B). In addition, consistent with the previous finding [15], we found that CYLD deficiency dramatically impaired sperm production; the density of sperm in CYLD knockout mice was much lower than that in wild-type mice ( Figure 1C). Examination of sperm swimming trajectories with time-lapse microscopy revealed that CYLD was critically required for sperm motility ( Figure 1D).…”

“…Consistent with the critical function of CYLD in ciliogenesis, CYLD-deficient mice exhibit several cilium-related disorders [13][14][15], together with polydactyly, as revealed in this study. The polydactylous symptom may result from the impairment of the Sonic hedgehog (Shh) pathway, a cilium-dependent pathway important for vertebrate limb development [31], since Shh-induced nuclear localization and transcriptional activity of the Gli family of proteins are decreased in CYLD siRNA-treated RPE-1 cells (Supplementary information, Figure S5).…”

“…CYLD also contains cytoskeleton-associated protein glycine-rich (CAP-Gly) domains that mediate its interaction with microtubules and histone deacetylase 6 (HDAC6) [10][11][12]. Several cilium-related symptoms, such as male infertility, osteoporosis, and impaired lung maturation, have been reported in CYLD knockout mice or in mice carrying truncated CYLD [13][14][15]. In addition, we found that a significant proportion of CYLD knockout mice had extra digits on the preaxial side of hind feet (Supplementary information, Figure S1), a condition frequently associated with ciliary abnormalities.…”

Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

“…38,39 Previously, it has been shown that CYLD promotes apoptosis or necrosis by blocking NF-κB signaling activity. 24,40,41 In addition, the NF-κB pathway is generally tightly regulated with a negative feedback loop, for instance, by the induction of SUMO protease SENP2 upon genotoxic stress to attenuate cell survival response. 42 This raises the possibility that SUMOylation of CYLD could be reversed after initiation of neuroblastoma differentiation by negative feedback loop.…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…RIP1 can subsequently be deubiquitylated by the enzyme, cylindromatosis (CYLD) (Wright et al, 2007), and together with RIP3, form a complex containing TRADD, FADD and caspase-8, called complex II (Micheau and Tschopp, 2003). The formation of complex II initiates the cell death signal and the decision between death via apoptosis or necroptosis is determined at this step.…”