Cell Death: Pulling the Apoptotic Trigger for Necrosis

RESEARCH HIGHLIGHTS

CELL DEATH GSDMD then oligomerizes and forms HEK293T cells generated DFNA5‑N pores in the plasma membrane and and induced secondary necrosis. thereby mediates necrotic cell death. The DFNA5‑N fragment was The authors found that another mem- also detected when apoptosis was Pulling the apoptotic ber of the gasdermin superfamily, induced in macrophages, which DFNA5, is also a caspase target, endogenously express DFNA5. trigger for necrosis but unlike GSDMD it is cleaved by These macrophages progressed caspase 3, the executioner caspase to secondary necrosis, which was Apoptosis and necrosis are considered of the apoptotic pathway. Akin to impaired in DFNA5‑deficient cells, to be distinct modes of cell death; GSDMD, this processing occurs at indicating that DFNA5 mediates however, apoptosis can progress secondary a single site (Asp270) and generates secondary necrosis and that its to secondary necrosis if apoptotic necrosis is amino-terminal (DFNA5‑N) and proteolytic processing downstream cells are not efficiently removed by carboxy-terminal (DFNA5‑C) of apoptotic stimuli is essential for phagocytic cells. Secondary necrosis a regulated portions of DFNA5. this activity. was thought to be unregulated and to process When DFNA5‑N was ectopically This work shows that DFNA5 is occur through passive cell swelling. expressed in human embryonic a substrate of caspase 3 and drives However, Rogers et al. now show that kidney 293T (HEK293T) cells, which necrosis after apoptosis induction, secondary necrosis is another exam- do not express endogenous DFNA5, revealing that secondary necrosis ple of programmed cell death and that the cells showed morphological and is a regulated process downstream it is triggered by apoptotic stimuli. biochemical features characteristic of apoptotic cell death. How this Apoptosis is executed by the of necrotic cells. DFNA5‑N was mode of cell death and its regulation activation of a cascade of proteolytic shown to associate with the plasma contribute to physiological and enzymes, the caspases. Pyroptosis membrane and computer modelling pathological processes remains to — a form of programmed necrosis approaches indicated that it can form be determined. induced by microbial infection — is pores, which indicates that DFNA5‑N Paulina Strzyz also activated by caspases (in this case generated through caspase 3 cleavage ORIGINAL ARTICLE Rogers, C. et al. Cleavage of inflammatory caspases), which are is an inducer of necrosis. DFNA5 by caspase‑3 during apoptosis mediates responsible for the proteolytic pro- Expression of DFNA5 (but not progression to secondary necrotic/pyroptotic cell cessing of gasdermin D (GSDMD). the non-cleavable mutant) and con- death. Nat. Commun. http://dx.doi.org/10.1038/ ncomms14128 (2017) The amino-terminal portion of comitant induction of apoptosis in Summersby/ V. Macmillan Publishers Limited

TRANSLATION in other cellular mRNAs, and ribosome profiling analyses further supported a Dhh1promotes role for Dhh1 in promoting translation translation initiation at these transcripts. Smoothening the coding Compared with other mRNAs, initiation of those that depend on Dhh1 for their sequence for translation ... mRNAs translation have longer and more that form structured coding sequences. Similarly, Remodelling of RNA structures by Next, through RNA–protein their human homologues also have proteins such as the DEAD-box (DDX) crosslinking and translation analyses, structures in relatively long, structured coding RNA helicases regulates gene expression the authors identified 245 yeast their coding sequences, and translation of one such at various stages. The budding transcripts that are bound by Dhh1, sequence mRNA, encoding the oncogene PTCH1, yeast helicase Dhh1 and its human and the translation of which is reduced was found to depend on DDX6. counterpart DDX6 are known to repress in cells lacking Dhh1. Binding of Dhh1 This study reveals a new mechanism of translation and activate mRNA decay. around the translation initiation codon translation regulation that is conserved Now, Jungfleisch et al. show that Dhh1 was much higher for these mRNAs than from yeast to humans. Relying on promotes translation initiation of a DDX helicases and on RNA structures, subset of mRNAs that form structures in including those present in coding their coding sequence. sequences, this mechanism controls The authors found in budding yeast translation initiation of specific genes that Dhh1 promotes translation and can be exploited by RNA viruses. initiation of the plant Brome mosaic Eytan Zlotorynski virus (BMV) RNA2 by binding to all ORIGINAL ARTICLE Jungfleisch, J. et al. A novel parts of the transcript. Because mRNA translational control mechanism involving RNA coding sequences have only rarely been structures within coding sequences. Genome Res. associated with translation regulation, http://dx.doi.org/10.1101/gr.209015.116 (2016) FURTHER READING Bourgeois, C. F., Mortreux, F. the authors focused on studying this part & Auboeuf, D. The multiple functions of RNA of the transcript and found a stem-loop helicases as drivers and regulators of gene structure that strongly inhibited its expression. Nat. Rev. Mol. Cell Biol. 17, 426–438 (2016) translation in cells lacking Dhh1. Lara Crow/ Macmillan Publishers Limited