Volume 5 (2021)
Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance
Beatrice Thier1,2 and Annette Paschen1,2
In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in (...)
To promote or inhibit glioma progression, that is the question for IL-33
Stephen M. Robbins1 and Donna L. Senger1
Glioblastoma represents one of the most fatal of human cancers. Although there has been progress in the treatment of glioblastoma as a result of a treatment regimen that combines maximal
p38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway
Clarissa Braun1,2, Karl Katholnig1, Christopher Kaltenecker3, Monika Linke1, Nyamdelger Sukhbaatar1, Markus Hengstschläger1 and Thomas Weichhart1
Programmed cell death protein 4 (PDCD4) exerts critical functions as tumor suppressor and in immune cells to regulate inflammatory processes. The phosphoinositide 3-kinase (PI3K) promotes degradation of PDCD4 via mammalian target of rapamycin complex 1 (mTORC1). However, additional pathways that may regulate PDCD4 expression are largely ill-defined. In this study, we have found that activation of the mitogen-activated protein kinase p38 promoted degradation of PDCD4 in macrophages and fibroblasts. Mechanistically, we identified a pathway from p38 and its substrate MAP kinase-activated protein kinase 2 (MK2) to the tuberous sclerosis complex (TSC) to regulate mTORC1-dependent (...)
Mechanisms of YAP/TAZ transcriptional control
Giusy Battilana1, Francesca Zanconato1 and Stefano Piccolo1,2
Dysregulated gene expression is intrinsic to cell transformation, tumorigenesis and metastasis. Cancer-specific gene-expression profiles stem from gene regulatory networks fueled by genetic and epigenetic defects, and by abnormal signals of the tumor microenvironment. These oncogenic signals ultimately engage the transcriptional machinery on the cis -regulatory elements of a host of effector genes, through recruitment of transcription factors (TFs), co-activators and chromatin regulators. That said, whether gene -expression in cancer cells is the chaotic product of myriad regulations or rather a relatively ordered process orchestrated by few TFs (master regulators) has long remained enigmatic. Recent work on the YAP/TAZ co-activators has been instrumental to break new ground into this outstanding issue, revealing that tumor cells hijack growth programs that are active during development and regeneration through engagement of a small set of interconnected TFs and their nuclear partners.
GRASPing the unconventional secretory machinery to bridge cellular stress signaling to the extracellular proteome
Constantinos Demetriades1,2, Julian Nüchel1 and Markus Plomann3
Part of the cellular response to stress is an evolutionarily conserved, poorly-understood process called unconventional protein secretion (UPS). Although cells shut down conventional/bulk secretion to save resources upon stress, UPS
Macroautophagy and normal aging of the nervous system: Lessons from animal models
Emmanouela Kallergi1 and Vassiliki Nikoletopoulou1
Aging represents a cumulative form of cellular stress, which is thought to challenge many aspects of proteostasis. The non-dividing, long-lived neurons are particularly vulnerable to stress, and, not surprisingly, even normal aging is highly associated with a decline in brain function in humans, as well as in other animals. Macroautophagy is a fundamental arm of the proteostasis network, safeguarding proper protein turnover during different cellular states and against diverse cellular stressors. An intricate interplay between macroautophagy and aging is beginning to unravel, with the emergence of new tools, including those for monitoring autophagy in cultured neurons and in the nervous system of different organisms in vivo. Here, we review recent findings on the impact of aging on neuronal integrity and on neuronal macroautophagy, as they emerge from studies in invertebrate and mammalian models.
Atg8ylation as a general membrane stress and remodeling response
Suresh Kumar1,2, Jingyue Jia1,2 and Vojo Deretic1,2
The yeast Atg8 protein and its paralogs in mammals, mammalian Atg8s (mAtg8s), have been primarily appreciated for their participation in autophagy. However, lipidated mAtg8s, including the most frequently used autophagosomal membrane marker LC3B, are found on cellular membranes other than autophagosomes. Here we put forward a hypothesis that the lipidation of mAtg8s, termed ‘Atg8ylation’, is a general membrane stress and remodeling response analogous to the role that ubiquitylation plays in tagging proteins. Ubiquitin and mAtg8s are related in sequence and structure, and the lipidation of mAtg8s occurs on its C-terminal glycine, akin to the C-terminal glycine of ubiquitin. Conceptually, we propose that mAtg8s and Atg8ylation are to membranes what ubiquitin and ubiquitylation are to proteins, and that, like ubiquitylation, Atg8ylation has a multitude of downstream effector outputs, one of which is autophagy.
Coping with the calcium overload caused by cell injury: ER to the rescue
Goutam Chandra1,2, Davi A. G. Mázala1,3 and Jyoti K. Jaiswal1,4
It was nearly a century ago that Lewis Victor Heilbrunn identified the requirement of extracellular Ca2+ for what he termed as ‘surface precipitation reaction‘, a process that allows the cytoplasm
Inhibitory DAMPs in immunogenic cell death and its clinical implications
Kazukuni Hayashi1,2, Fotis Nikolos3 and Keith S. Chan1,3
– [table id=388/] INHIBITORY DAMP OR INHIBITORY DAMPS? How are immunostimulatory DAMPs shut off? Under normal physiological conditions, the co-stimulatory molecules, CD80/86, on antigen presenting cells bind to the co-activating
Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases
Valentina Sala1, Angela Della Sala1, Alessandra Ghigo1,2,# and Emilio Hirsch1,2,#
Phosphatidyl inositol 3 kinase gamma (PI3Kγ) is expressed in all the cell types that are involved in airway inflammation and disease, including not only leukocytes, but also structural cells, where it is expressed at very low levels under physiological conditions, while is significantly upregulated after stress. In the airways, PI3Kγ behaves as a trigger or a controller, depending on the pathological context. In this review, the contribution of PI3Kγ in a plethora of respiratory diseases, spanning from acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis and response to both bacterial and viral pathogens, will be commented.
The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle
Manuela Morleo1 and Brunella Franco1,2
Autophagy is an evolutionary conserved and highly regulated cellular degradation pathway which entails the engulfment of cellular components into double-membrane vesicles, called autophagosomes, which then fuse with lysosomes to degrade
Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance
Beatrice Thier1,2 and Annette Paschen1,2
In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in (...)
Spermidine supplementation in rare translation-associated disorders
Andreas Zimmermann1,2, Didac Carmona-Gutierrez1, and Frank Madeo1,2,3
Spermidine is a naturally occurring polyamine that is strongly involved in manifold cellular processes, for example, DNA, RNA and protein stabilization, cell growth, proliferation, autophagy, and aging. Importantly, spermidine has