Aggregability of the SQSTM1/p62-based aggresome-like induced structures determines the sensitivity to parthanatos.

Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) triggers a noncanonical form of programmed cell death (PCD) called parthanatos, yet the mechanisms of its induction are not fully understood. We have recently demonstrated that the aggresome-like induced structures (ALIS) composed of the autophagy receptor SQSTM1/p62 and K48-linked polyubiquitinated proteins (p62-based ALIS) mediate parthanatos. In this study, we identified the D1 dopamine receptor agonist YM435 as a unique parthanatos inhibitor that acts as the disaggregating agent for the p62-based ALIS. We found that YM435 structurally reduces aggregability of the ALIS, and then increases its hydrophilicity and liquidity, which prevents parthanatos. Moreover, dopamine and L-DOPA, a dopamine precursor, also prevented parthanatos by reducing the aggregability of the ALIS. Together, these observations suggest that aggregability of the p62-based ALIS determines the sensitivity to parthanatos, and the pharmacological properties of YM435 that reduces the aggregability may be suitable for therapeutic drugs for parthanatos-related diseases such as neurodegenerative diseases.

The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin.

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.

The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages.

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-1ß (IL-1ß) was stimulated. Interestingly, PMB-induced IL-1ß 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-1ß 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.