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  • Introduction Apoptosis signal regulating kinase

    2023-11-23

    Introduction Apoptosis signal-regulating kinase 1 (ASK1), a family member of the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, selectively activates the JNK and p38 MAP kinase pathways in response to various types of stresses, including oxidative stress, and subsequently induces multiple cellular responses, such as cell death and mps1 (Ichijo et al., 1997, Matsuzawa et al., 2005, Noguchi et al., 2008, Tobiume et al., 2001). Accumulating evidence suggests that ASK1 is involved in the pathogenesis of diseases, including inflammatory diseases, cancers, and neurodegenerative diseases (Matsuzawa et al., 2005, Nakagawa et al., 2011, Nishitoh et al., 2008, Osaka et al., 2007, Soga et al., 2012). Therefore, elucidating the mechanism by which ASK1 activity is regulated may lead to an understanding of the molecular basis for ASK1-related diseases and facilitate the development of therapies for these diseases. One of the most potent ASK1-activating stimuli is oxidative stress, and the molecular mechanisms underlying oxidative stress-induced ASK1 activation have been characterized extensively. In unstimulated cells, ASK1 is kept inactive through the interaction with reduced thioredoxin (Trx), a negative regulator of ASK1. Under oxidative stress, Trx is oxidized and dissociates from ASK1, which induces autophosphorylation of ASK1 (Thr838 and Thr845 of human and mouse ASK1, respectively) by triggering the recruitment of ASK1 activators, namely, tumor necrosis factor (TNF) receptor-associated factors (TRAFs), such as TRAF2 and TRAF6 (Fujino et al., 2007, Nishitoh et al., 1998, Noguchi et al., 2005, Saitoh et al., 1998). Phosphorylated ASK1 is negatively regulated by the serine/threonine protein phosphatase 5 (PP5), which directly dephosphorylates an important threonine residue, thereby inactivating ASK1 (Morita et al., 2001). Thus, ASK1 activity is regulated by its binding proteins through modulation of its phosphorylation status. We recently reported that ASK1 is also regulated by its amount through modulation of its ubiquitination status (Maruyama et al., 2014, Nagai et al., 2009). We found that oxidative stress induces ubiquitination-dependent degradation of oxidative stress-activated ASK1, and that the ubiquitin-specific protease 9X (USP9X) counteracts the proteasomal degradation of ASK1 by deubiquitination (Nagai et al., 2009). In USP9X-knockdown cells, oxidative stress-induced JNK and p38 activation and, ultimately, cell death were suppressed, suggesting that ubiquitination/deubiquitination machinery plays a key role in regulating ASK1 activation. To elucidate the regulatory mechanisms underlying ASK1 ubiquitination further, we performed a functional small interfering RNA (siRNA) screen designed to identify the E3 ubiquitin ligase responsible for oxidative stress-induced ASK1 degradation and identified a candidate Roquin-2 (also known as RC3H2) (Maruyama et al., 2014). We showed that Roquin-2 interacts with oxidative stress-activated ASK1 and promotes its ubiquitination and degradation. Roquin-2 knockdown facilitated oxidative stress-induced JNK and p38 activation and cell death. Thus, we determined that Roquin-2 is the E3 ubiquitin ligase responsible for ASK1 ubiquitination. In the functional siRNA screen, we also identified tripartite motif 48 (TRIM48) as a candidate E3 ubiquitin ligase that regulates ASK1 (Maruyama et al., 2014). TRIM48 has a RING-finger motif with E3 ubiquitin ligase activity and belongs to the TRIM family. TRIM family is characterized by three conserved domains or motifs (a RING-finger motif, a B-box domain, and a coiled-coil domain), whereas TRIM48 lacks the coiled-coil domain. The TRIM family comprises nearly 100 members in humans, and several of these proteins have been reported to function as E3 ubiquitin ligases that mediate a wide range of biological functions, such as cell death and innate immune responses (Han et al., 2011, Ozato et al., 2008). Several TRIM genes in the TRIM family are conserved only in primates (humans and African apes). These genes arose during primate evolution through segmental duplication. Notably, TRIM48 is one of the 7 human-specific genes (Han et al., 2011). These genes are predicted to encode proteins that function as E3 ubiquitin ligases; however, to date, there have been no reports regarding the molecular or biological functions of these human-specific TRIM family members, and how TRIM48 contributes to the promotion of oxidative stress-induced ASK1 degradation remains to be elucidated.