Yin Yang 1 (YY1), a dual function transcription factor, is known to regulate transcriptional activation and repression of many genes associated with multiple cellular processes including cellular ...differentiation, DNA repair, autophagy, cell survival vs. apoptosis, and cell division. Owing to its role in processes that upon deregulation are linked to malignant transformation, YY1 has been implicated as a major driver of many cancers. While a large body of evidence supports the role of YY1 as a tumor promoter, recent reports indicated that YY1 also functions as a tumor suppressor. The mechanism by which YY1 brings out opposing outcome in tumor growth vs. suppression is not completely clear and some of the recent reports have provided significant insight into this. Likewise, the mechanism by which YY1 functions both as a transcriptional activator and repressor is not completely clear. It is likely that the proteins with which YY1 interacts might determine its function as an activator or repressor of transcription as well as its role as a tumor suppressor or promoter. Hence, a collection of YY1-protein interactions in the context of different cancers would help us gain an insight into how YY1 promotes or suppresses cancers. This review focuses on the YY1 interacting partners and its target genes in different cancer models. Finally, we discuss the possibility of therapeutically targeting the YY1 in cancers where it functions as a tumor promoter.
Several large-scale genome-wide association studies genetically linked IRGM to Crohn’s disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the ...mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1β maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn’s disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.
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•IRGM negatively regulates NLRP3/ASC inflammasome activation•IRGM obstructs NLRP3/ASC inflammasome assembly•IRGM mediates selective autophagic degradation of NLRP3/ASC inflammasome•Irgm1 by suppressing Nlrp3 inflammasome prevents gut inflammation in an IBD mouse model
The IRGM is an established genetic risk factor for Crohn’s diseases and several other inflammatory disorders. Mehto et al. show that IRGM inhibits NLRP3 inflammasome activation to keep the inflammation under check. This study provides a basis for the protective function of IRGM in inflammatory diseases.
Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms ...controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress‐induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62‐NRF2 axis. We show that TRIM16 is an integral part of the p62‐KEAP1‐NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. Thus, TRIM16 streamlines the process of stress‐induced aggregate clearance and protects cells against oxidative/proteotoxic stress‐induced toxicity in vitro and in vivo. Taken together, this work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation‐associated diseases such as neurodegeneration.
Synopsis
The tripartite motif‐containing ubiquitin ligase TRIM16 governs the stress‐induced formation of protein aggregate by regulating the NRF2 stress response pathway, and also mediates degradation of protein aggregates by engaging the autophagy machinery.
TRIM16 associates with p62‐NRF2 complex to positively regulate its activity.
TRIM16 and NRF2 governs the process of stress‐induced biogenesis of protein aggregates.
TRIM16 acts as a scaffold protein to assemble the autophagy machinery for degradation of protein aggregates.
TRIM16 protects cells from oxidative and proteotoxic stress‐induced cytotoxicity in vitro and in vivo.
A tripartite motif‐containing ubiquitin ligase modifies the p62‐NRF2 complex for stress‐induced protein aggregation and provides an assembly scaffold for autophagy factors involved in aggregate clearance.
Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to ...several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS‐STING and RIG‐I‐MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
Synopsis
Loss of function of IRGM has been linked to the pathogenesis of several autoimmune diseases. This study shows that IRGM is a master repressor of interferon responses by controlling mitophagy and selective autophagy of nucleic acid sensors.
Immunity Related GTPase M (IRGM) maintains homeostatic balance of interferon responses.
IRGM suppresses interferon signaling via p62‐dependent autophagic degradation of cGAS, RIG‐I, and TLR3.
IRGM deficiency results in defective mitophagy and mito‐DAMP release, driving interferon responses.
Loss of function of IRGM has been linked to the pathogenesis of several autoimmune diseases. This study shows that IRGM is a master repressor of interferon responses by controlling mitophagy and selective autophagy of nucleic acid sensors.
Oncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves ...alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.
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•Ribosomes are selectively degraded by autophagy during oncogene-induced senescence•USP10 dissociation from the ribosome triggers ribosome turnover in senescence•The p62 receptor mediates degradation of ubiquitinated ribosomes in senescence•Ribosome turnover by autophagy fuels the senescence-associated secretory phenotype
López et al. demonstrate that ribosomes are selectively degraded by autophagy during oncogene-induced senescence. This is mediated by the release of USP10 from the ribosome, leading to enhanced ribosome ubiquitination. The p62 receptor recognizes ubiquitinated ribosomes and mediates their turnover. This process facilitates senescence-associated metabolome and secretome remodeling.
During autophagy, the ATG8 family proteins have several well-characterized roles in facilitating early, mid, and late steps of autophagy, including autophagosome expansion, cargo recruitment and ...autophagosome-lysosome fusion. Their discovery has importantly allowed for precise experimental monitoring of the pathway, bringing about a huge expansion of research in the field over the last decades. In this review, we discuss both canonical and non-canonical roles of the autophagic lipidation machinery, with particular focus on the ATG8 proteins, their post-translational modifications and their increasingly uncovered alternative roles mediated through their anchoring at different membranes. These include endosomes, macropinosomes, phagosomes and the plasma membrane, to which ATG8 proteins can bind through canonical or alternative lipidation. Beyond new ATG8 binding partners and cargo types, we also explore several open questions related to alternative outcomes of autophagic machinery engagement beyond degradation. These include their roles in plasma membrane repair and secretion of selected substrates as well as the physiological implications hereof in health and disease.
Acute myeloid leukemia (AML) is a common and aggressive hematological malignancy. Acquisition of heterogeneous genetic aberrations and epigenetic dysregulation lead to the transformation of ...hematopoietic stem cells (HSC) into leukemic stem cells (LSC), which subsequently gives rise to immature blast cells and a leukemic phenotype. LSCs are responsible for disease relapse as current chemotherapeutic regimens are not able to completely eradicate these cellular sub-populations. Therefore, it is critical to improve upon the existing knowledge of LSC specific markers, which would allow for specific targeting of these cells more effectively allowing for their sustained eradication from the cellular milieu. Although significant milestones in decoding the aberrant transcriptional network of various cancers, including leukemia, have been achieved, studies on the involvement of post-transcriptional gene regulation (PTGR) in disease progression are beginning to unfold. RNA binding proteins (RBPs) are key players in mediating PTGR and they regulate the intracellular fate of individual transcripts, from their biogenesis to RNA metabolism, via interactions with RNA binding domains (RBDs). In this study, we have used an integrative approach to systematically profile RBP expression and identify key regulatory RBPs involved in normal myeloid development and AML. We have analyzed RNA-seq datasets (GSE74246) of HSCs, common myeloid progenitors (CMPs), granulocyte-macrophage progenitors (GMPs), monocytes, LSCs, and blasts. We observed that normal and leukemic cells can be distinguished on the basis of RBP expression, which is indicative of their ability to define cellular identity, similar to transcription factors. We identified that distinctly co-expressing modules of RBPs and their subclasses were enriched in hematopoietic stem/progenitor (HSPCs) and differentiated monocytes. We detected expression of DZIP3, an E3 ubiquitin ligase, in HSPCs, knockdown of which promotes monocytic differentiation in cell line model. We identified co-expression modules of RBP genes in LSCs and among these, distinct modules of RBP genes with high and low expression. The expression of several AML-specific RBPs were also validated by quantitative polymerase chain reaction. Network analysis identified densely connected hubs of ribosomal RBP genes (rRBPs) with low expression in LSCs, suggesting the dependency of LSCs on altered ribosome dynamics. In conclusion, our systematic analysis elucidates the RBP transcriptomic landscape in normal and malignant myelopoiesis, and highlights the functional consequences that may result from perturbation of RBP gene expression in these cellular landscapes.
Colorectal cancer (CRC) is the third most common cancer; cancer biomarker discovery is important for disease detection and management. It is known that hyaluronic acid and its receptors are ...ubiquitously expressed in almost all human tissues. Earlier we have shown that a monoclonal antibody H11B2C2, presently known as UNIVmAb, reactive hyaladherin expressed in multiple human cancers mainly using immunohistochemistry. However, the nature of the antigen and its sequence homology are not known. In the current study, a comprehensive investigation was performed to explore the nature of the antigen and its homology using both biochemical and proteomic analysis. Our results showed that UNIVmAb reactive 57 kDa antigen was overexpressed in advanced grade colorectal cancer tissues compared to benign and its hyperplasia. Biochemical investigations including biotinylated hyaluronic acid-pulldown, Immunoprecipitation, HA-oligo competition experiments confirmed that the UNIVmAb reactive 57 kDa antigen is a member of hyaladherin. Further Proteomic analysis showed that the antigen has homology with IGHG1 (Igγ-1 chain C region), a possible IgG superfamily, and is associated with human serum albumin.
Protein misfolding and protein aggregation are linked to several diseases commonly called as proteinopathies, which include cancer. Understanding the mechanisms of proteostasis could provide newer ...strategies to combat proteinopathies. We have recently demonstrated a new mechanism where we found that TRIM16 (tripartite motif-containing protein 16) utilizing NRF2-p62 axis and autophagy streamlines the safe disposal of misfolded proteins to maintain protein homeostasis.
The cellular stresses, genetic mutations, and environmental factors can critically affect the protein quality control checkpoints resulting in protein misfolding. Molecular chaperones play a crucial ...role in maintaining the healthy proteome by refolding the misfolded proteins into the native functional conformations. However, if they fail to refold the misfolded proteins into the native state, they are targeted by proteolytic systems for degradation. If the misfolded protein numbers increase more than what a cell can resolve, they get converted protein aggregates/inclusion bodies. The inclusion bodies are less cytotoxic than misfolded proteins. The enhanced production of misfolded proteins and protein aggregates are linked to several diseases collectively termed proteinopathies, which includes several neurodegenerative disorders. The understanding of molecular mechanisms that regulate the turnover of protein aggregates will pave path for therapeutic interventions of proteinopathies. In a recent report, we showed that a tripartite motif (TRIM) family protein, TRIM16 streamlines the process of protein aggregates turnover by regulating the NRF2-p62 axis and autophagy.
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