The role of SPATA2 in TNF signaling, cancer, and spermatogenesis

Abstract

The activation of TNF receptors can lead to cell death with a mechanism of cell necrosis regulated genetically and distinct from apoptosis which is defined as necroptosis. Necroptosis has been one of the most studied emerging cell death/signaling pathways in recent years, especially in light of the role of this process in human disease. However, not all regulatory components of TNF signaling have been identified in relation to both physiological and pathological conditions. In 2008, Spata2 (Spermatogenesis-associated protein 2) was identified as one of the seven fundamental genes for the cellular signaling network that regulates necroptosis and apoptosis. This gene had been cloned by our group and named Spata2 as its expression was found to be elevated in the testis compared to other tissues, localized at the Sertoli cell level and FSH-dependent. More recently, it has been demonstrated that deletion of Spata2 gene causes increased inhibin α expression and attenuated fertility in male mice. However, more importantly, five recently published reports have highlighted that SPATA2 is crucial for recruiting CYLD to the TNFR1 signaling complex thus promoting its activation leading to TNF-induced cell death. Loss of SPATA2 increases transcriptional activation of NF-kB and limits TNF-induced necroptosis. Here we will discuss these important findings regarding SPATA2 and, in particular, focus attention on the evidence that suggests a role for this protein in the TNF signaling pathway.

Fig. 1. Role of SPATA2 at the level of TNF-RSC.

After stimulation by TNFα (1), the CYLD/SPATA2/LUBAC complex (just pre-existing in the cytosol (2) is recruited into the receptor complex I through the interaction of LUBAC with the ubiquitin chains present in the complex (3). At the same time, the direct interaction of SPATA2 with CYLD results in an increase in the enzymatic activity of the latter which mediates the de-ubiquitylation (4) of some complex components such as RIPK1–thus playing a fundamental role in attenuating the signaling pathway triggered by TNFα. Therefore, activated CYLD attenuates NF-kB pro-inflammatory signaling and MAPK pro-cell-survival response (5). Alternatively, a second complex (named complex 2) can form by recruiting, among other factors, RIPK1, FADD, and caspase-8–thus resulting in the induction of apoptotic cell death (6). If caspase-8 is inhibited, assembly following TNF stimulation promotes an alternative complex 2 with MLKL leading to necroptotic cell death (7).

Fig. 2. Immunohistochemical localization of SPATA2 at the Sertoli cell level.

The expression of SPATA2 is highlighted as a brown color that is localized in correspondence with the cytoplasm of Sertoli cells (indicated by arrows) which are easily recognizable by their elongated and branched shape and by an ovoid nucleus with the evident nucleolus. No positivity was observed in any cell of the spermatogenic germline. Scale bar = 20 μm.