Cleavage of the gasdermins to produce a pore-forming N-terminal fragment causes inflammatory death (pyroptosis) 1 . Caspase-3 cleaves gasdermin E (GSDME, also known as DFNA5), mutated in familial aging-related hearing loss 2 , which converts noninflammatory apoptosis to pyroptosis in GSDME-expressing cells 3 – 5 . GSDME expression is suppressed in many cancers and reduced GSDME is associated with decreased breast cancer survival 2 , 6 , suggesting GSDME might be a tumor suppressor. Here we show reduced GSDME function of 20 of 22 tested cancer-associated mutations. Gsdme knockout in GSDME-expressing tumors enhances, while ectopic expression in Gsdme -repressed tumors inhibits, tumor growth. Tumor suppression is mediated by cytotoxic lymphocyte killing since it is abrogated in perforin-deficient or killer lymphocyte-depleted mice. GSDME expression enhances tumor-associated macrophage phagocytosis and the number and functions of tumor-infiltrating NK and CD8 + T lymphocytes. Killer cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase-3. Non-cleavable or pore-defective GSDME are not tumor suppressive. Thus, tumor GSDME is a tumor suppressor by activating pyroptosis, which enhances anti-tumor immunity.

Gene expression regulation is essential for correct functioning of the cell. Complex processes such as development, apoptosis, cell differentiation, and cell cycling require a fine tuning of gene expression. MicroRNAs (miRNAs) are small RNAs that have been recognized as key components of the gene expression regulatory machinery. By sequence complementarity, miRNAs recognize target mRNAs and inhibit their function through degradation or by repressing their translation. The development of the central nervous system (CNS) requires precise and exquisitely regulated gene expression patterns. It is now widely recognized that miRNAs have the capacity to provide such fine regulation both in time and in space. High-throughput analyses as well as classical molecular biology approaches have allowed the identification of essential miRNAs for CNS development and function. Moreover, recent studies in several model organisms are beginning to show intricate regulatory networks involving miRNAs, transcription factors, and epigenetic regulators during CNS development. Here we review recent findings on the role that miRNAs play in the development of the CNS as well as in neuropathologies such as schizophrenia, Parkinson disease, and Alzheimer's disease, among others.

Development of the central nervous system (CNS) requires a precisely coordinated series of events. During embryonic development, different intra- and extracellular signals stimulate neural stem cells to become neural progenitors, which eventually irreversibly exit from the cell cycle to begin the first stage of neurogenesis. However, before this event occurs, the self-renewal and proliferative capacities of neural stem cells and neural progenitors must be tightly regulated. Accordingly, the participation of various evolutionary conserved microRNAs is key in distinct central nervous system (CNS) developmental processes of many organisms including human, mouse, chicken, frog, and zebrafish. microRNAs specifically recognize and regulate the expression of target mRNAs by sequence complementarity within the mRNAs 3′ untranslated region and importantly, a single microRNA can have several target mRNAs to regulate a process; likewise, a unique mRNA can be targeted by more than one microRNA. Thus, by regulating different target genes, microRNAs let-7, microRNA-124, and microRNA-9 have been shown to promote the differentiation of neural stem cells and neural progenitors into specific neural cell types while microRNA-134, microRNA-25 and microRNA-137 have been characterized as microRNAs that induce the proliferation of neural stem cells and neural progenitors. Here we review the mechanisms of action of these two sets of microRNAs and their functional implications during the transition from neural stem cells and neural progenitors to fully differentiated neurons. The genetic and epigenetic mechanisms that regulate the expression of these microRNAs as well as the role of the recently described natural RNA circles which act as natural microRNA sponges regulating post-transcriptional microRNA expression and function during the early stages of neurogenesis is also discussed.

Widespread mRNA decay, an unappreciated feature of apoptosis, enhances cell death and depends on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2. Which RNAs are decayed and the decay-initiating event are unknown. Here, we show extensive decay of mRNAs and poly(A) noncoding (nc)RNAs at the 3' end, triggered by the mitochondrial intermembrane space 3'-to-5' exoribonuclease PNPT1, released during MOMP. PNPT1 knockdown inhibits apoptotic RNA decay and reduces apoptosis, while ectopic expression of PNPT1, but not an RNase-deficient mutant, increases RNA decay and cell death. The 3' end of PNPT1 substrates thread through a narrow channel. Many non-poly(A) ncRNAs contain 3'-secondary structures or bind proteins that may block PNPT1 activity. Indeed, mutations that disrupt the 3'-stem-loop of a decay-resistant ncRNA render the transcript susceptible, while adding a 3'-stem-loop to an mRNA prevents its decay. Thus, PNPT1 release from mitochondria during MOMP initiates apoptotic decay of RNAs lacking 3'-structures.

In addition to its roles in controlling infection and tissue repair, inflammation plays a critical role in diverse and distinct chronic diseases, such as cancer, metabolic syndrome, and neurodegenerative disorders, underscoring the harmful effect of an uncontrolled inflammatory response. Regardless of the nature of the stimulus, initiation of the inflammatory response is mediated by assembly of a multimolecular protein complex called the inflammasome, which is responsible for the production of inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. The different stimuli and mechanisms that control inflammasome activation are fairly well understood, but the mechanisms underlying the control of undesired inflammasome activation and its inactivation remain largely unknown. Here, we review recent advances in our understanding of the molecular mechanisms that negatively regulate inflammasome activation to prevent unwanted activation in the resting state, as well as those involved in terminating the inflammatory response after a specific insult to maintain homeostasis.

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression and their misregulation is common in different types of cancer. Although it has been shown that miR-7 plays an oncogenic role in different cellular contexts, the molecular mechanisms by which miR-7 promotes cell transformation are not well understood. Here we show that the transcription factor KLF4 is a direct target of miR-7 and present experimental evidence indicating that the regulation of KLF4 by miR-7 has functional implications in epithelial cell transformation. Stable overexpression of miR-7 into lung and skin epithelial cells enhanced cell proliferation, cell migration and tumor formation. Alteration of these cellular functions by miR-7 resulted from misregulation of KLF4 target genes involved in cell cycle control. miR-7-induced tumors showed decreased p21 and increased Cyclin D levels. Taken together, these findings indicate that miR-7 acts as an oncomiR in epithelial cells in part by directly regulating KLF4 expression. Thus, we conclude that miR-7 acts as an oncomiR in the epithelial cellular context, where through the negative regulation of KLF4-dependent signaling pathways, miR-7 promotes cellular transformation and tumor growth.

New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM+ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2+ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti–PD-1 checkpoint inhibition.

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