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Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that is activated by growth factors and cytokines such as TGF-β, IL-1β, and TNF-α, and mediates a wide range of biological processes through activation of the nuclear factor-κB (NF-κB) and the mitogen-activated protein (MAP) kinase signaling pathways. It is well established that activation status of TAK1 is tightly regulated by forming a complex with its binding partners, TAK1-binding proteins (TAB1, TAB2, and TAB3). Interestingly, recent evidence indicates the importance of post-translational modifications (PTMs) of TAK1 and TABs in the regulation of TAK1 activation. To date, a number of PTMs of TAK1 and TABs have been revealed, and these PTMs appear to fine-tune and coordinate TAK1 activities depending on the cellular context. This review therefore focuses on recent advances in the understanding of the PTMs of the TAK1-TAB complex.

Polymyxin B (PMB) is an essential antibiotic active against multidrug-resistant bacteria, such as multidrug-resistant Pseudomonas aeruginosa (MDRP). However, the clinical use of PMB is limited, because PMB causes serious side effects, such as nephrotoxicity and neurotoxicity, probably due to its cytotoxic activity. However, cytotoxic mechanisms of PMB are poorly understood. In this study, we found that macrophages are particularly sensitive to PMB, when compared with other types of cells, including fibroblasts and proximal tubule (PT) cells. Of note, PMB-induced necrosis of macrophages allowed passive release of high mobility group box 1 (HMGB1). Moreover, upon exposure of PMB to macrophages, the innate immune system mediated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome that promotes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) was stimulated. Interestingly, PMB-induced IL-1β release occurred in the absence of the pore-forming protein gasdermin D (GSDMD), which supports the idea that PMB causes plasma membrane rupture accompanying necrosis. Emerging evidence has suggested that both HMGB1 and IL-1β released from macrophages contribute to excessive inflammation that promote pathogenesis of various diseases, including nephrotoxicity and neurotoxicity. Therefore, these biochemical properties of PMB in macrophages may be associated with the induction of the adverse organ toxicity, which provides novel insights into the mechanisms of PMB-related side effects.

trans -Fatty acids (TFAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)-interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders.

Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR.

Anticancer drug gefitinib causes inflammation-based side effects, such as interstitial pneumonitis. However, its mechanisms remain unknown. Here, we provide evidence that gefitinib elicits pro-inflammatory responses by promoting mature-interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release. Mitochondrial reactive oxygen species (mtROS) driven by gefitinib stimulated the formation of the NLRP3 (NACHT, LRR and PYD-containing protein 3) inflammasome, leading to mature-IL-1β release. Notably, gefitinib also stimulated HMGB1 release, which is, however, not mediated by the NLRP3 inflammasome. On the other hand, gefitinib-driven mtROS promoted the accumulation of γH2AX, a hallmark of DNA damage, leading to the activation of poly (ADP-ribose) polymerase-1 (PARP-1) and subsequent active release of HMGB1. Together our results reveal the potential ability of gefitinib to initiate sterile inflammation via two distinct mechanisms, and identified IL-1β and HMGB1 as key determinants of gefitinib-induced inflammation that may provide insights into gefitinib-induced interstitial pneumonitis.

trans -Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

trans -Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon–carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.

Polymyxin B (PMB), a last-line antibiotic used against antibiotic-resistant superbugs, causes undesirable cytotoxic side effects. However, its mechanisms remain unknown. In this study, we unexpectedly found that caspase-3, a main executor of apoptosis, plays a protective role in PMB-induced cytotoxicity. Caspase-3 knockout (KO) cells exhibited higher susceptibility to PMB-induced cytotoxicity compared with wild-type (WT) cells, accompanied by increased levels of reactive oxygen species (ROS). Interestingly, co-treatment with the antioxidant N-acetylcysteine (NAC) rescued cell viability to a similar extent as WT cells. Furthermore, PMB failed to facilitate the processing of inactive caspase-3 (pro-caspase-3) into active forms, suggesting that pro-caspase-3 nonenzymatically suppresses PMB-driven ROS accumulation and its cytotoxicity. Thus, our findings that demonstrate the potential ability of PMB to stimulate ROS generation, but which is normally masked by pro-caspase-3-dependent mechanisms, may provide novel insights into the mechanisms of PMB-induced side effects.

Parthanatos represents an alternative form of regulated cell death (RCD) mediated by poly (ADP-ribose) polymerase-1 (PARP-1). However, the underlying mechanisms and physiological significance of parthanatos are poorly understood. In this study, we investigated molecular mechanisms of parthanatos in human fibrosarcoma HT1080 cells using biochemical and cellular experiments, and found that parthanatos induced by the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) is mediated by two alternative pathways that depend on pro-death Bcl-2 family proteins BAX/BAK or Bcl-2-interacting mediator of cell death (Bim). Moreover, we found that MNNG activates AMP-activated protein kinase (AMPK) through PARP-1-dependent ATP depletion, and then AMPK selectively downregulates MNNG-induced parthanatos mediated by Bim but not BAX/BAK. Under unstimulated conditions, expression levels of Bim were below the detection limit. Interestingly, MNNG strongly upregulated the protein expression levels of Bim, but only when the activation of AMPK was inhibited. These observations suggest that the AMPK signaling pathways activated by PARP-1-dependent ATP depletion limit parthanatos by blocking the Bim upregulation triggering Bim-mediated parthanatos. Thus, our results demonstrate a novel relationship between AMPK and parthanatos, which may provide insights into the physiological roles of parthanatos.

It is known that a wide variety of antibacterial agents stimulate generation of reactive oxygen species (ROS) in mammalian cells. However, its mechanisms are largely unknown. In this study, we unexpectedly found that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is involved in the generation of mitochondrial ROS (mtROS) initiated by cefotaxime (CTX), one of specific antibacterial cephalosporins that can trigger oxidative stress-induced cell death. TAK1-deficient macrophages were found to be sensitive to oxidative stress-induced cell death stimulated by H2O2. Curiously, however, TAK1-deficient macrophages exhibited strong resistance to oxidative stress-induced cell death stimulated by CTX. Microscopic analysis revealed that CTX-induced ROS generation was overridden by knockout or inhibition of TAK1, suggesting that the kinase activity of TAK1 is required for CTX-induced ROS generation. Interestingly, pharmacological blockade of the TAK1 downstream pathways, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, did not affect the CTX-induced ROS generation. In addition, we observed that CTX promotes translocation of TAK1 to mitochondria. Together, these observations suggest that mitochondrial TAK1 mediates the CTX-induced mtROS generation through noncanonical mechanisms. Thus, our data demonstrate a novel and atypical function of TAK1 that mediates mtROS generation triggered by the specific cephalosporins.