Volume 4 (2020)
Copper – a novel stimulator of autophagy
Hans Zischka1,2 and Guido Kroemer3-7
In biomedicine, the transition metal copper has a Janus-faced dual role, as an essential but static cofactor of vital enzymes but also as a highly detrimental poison, if in excess.
Towards understanding the role of Receptor Expression Enhancing Protein 5 (REEP5) in cardiac muscle and beyond
Shin-Haw Lee1,2, Sina Hadipour-Lakmehsari1,2 and Anthony O. Gramolini1,2
DISCOVERY OF REEP5 Cardiac membrane proteins play an important role in regulating normal beat-to-beat function of the heart given their importance in coordinating spontaneous contractions of cardiomyocytes in the heart.
Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases
Gina Picchiarelli1 and Luc Dupuis1
A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.
HIF1α-dependent mitophagy facilitates cardiomyoblast differentiation
Jin-Feng Zhao1,#, Catherine E. Rodger1,#, George F. G. Allen1, Simone Weidlich1 and Ian G. Ganley1
Mitophagy is thought to play a key role in eliminating damaged mitochondria, with diseases such as cancer and neurodegeneration exhibiting defects in this process. Mitophagy is also involved in cell differentiation and maturation, potentially through modulating mitochondrial metabolic reprogramming. Here we examined mitophagy that is induced upon iron chelation and found that the transcriptional activity of HIF1α, in part through upregulation of BNIP3 and NIX, is an essential mediator of this pathway in SH-SY5Y cells. In contrast, HIF1α is dispensable for mitophagy occurring upon mitochondrial depolarisation. To examine the role of this pathway in a metabolic reprogramming and differentiation context, we utilised the H9c2 cell line model of cardiomyocyte maturation. During differentiation of these cardiomyoblasts, mitophagy increased and required HIF1α-dependent upregulation of NIX. Though HIF1α was essential for expression of key (...)
Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses
Didier Raoult1, Alimuddin Zumla2,3, Franco Locatelli4, Giuseppe Ippolito5 and Guido Kroemer6-10,*
INTRODUCTION Infections have been limiting quality of life and longevity throughout human history. Endemic infections have been associated to a significant number of avoidable deaths and a significant increase of
Biomechanical stress regulates mammalian tooth replacement
Xiaoshan Wu1,2 and Songlin Wang1,3
The DT eruption released a biomechanical stress of about 3-20 kPa inside the mandible. By culturing the mandible slice in vitro, the SDL of the PT immediately transitioned into the
Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders
Christian Hiepen1, Jerome Jatzlau1 and Petra Knaus1
BMPR2 MUTATIONS PRIME FOR PAH BUT REQUIRE A SECOND HIT While BMPR2 mutations appear as one of the main genetic drivers for HPAH, low BMPR2 expression is also found in
ACBP is an appetite stimulator across phylogenetic barriers
Frank Madeo1,2, Nektarios Tavernarakis3,4, José M. Bravo-San Pedro5-7,# and Guido Kroemer5-10,#
Human civilization is unique with respect to the organization of our natural environment, allowing constant supply of nutrients to most individuals in developed countries, contrasting with the natural fluctuation in
RPA and Pif1 cooperate to remove G-rich structures at both leading and lagging strand
Laetitia Maestroni1, Julien Audry1, Pierre Luciano1, Stéphane Coulon1, Vincent Géli1 and Yves Corda1
In Saccharomyces cerevisiae, the absence of Pif1 helicase induces the instability of G4-containing CEB1 minisatellite during leading strand but not lagging strand replication. We report that RPA and Pif1 cooperate to maintain CEB1 stability when the G4 forming strand is either on the leading or lagging strand templates. At the leading strand, RPA acts in the same pathway as Pif1 to maintain CEB1 stability. Consistent with this result, RPA co-precipitates with Pif1. This association between Pif1 and RPA is affected by the rfa1-D228Y mutation that lowers the affinity of RPA in particular for G-rich single-stranded DNA. At the lagging strand, in contrast to pif1∆, the rfa1-D228Y mutation strongly increases the frequency of CEB1 rearrangements. We explain that Pif1 is dispensable at the lagging strand DNA by the ability of RPA by itself to prevent formation of stable G-rich secondary structures during lagging (…)
Exocytotic fusion pore under stress
Helena Haque Chowdhury1,2 and Robert Zorec1,2
Exocytosis is a universal process of eukaryotic cells, consisting of fusion between the vesicle and the plasma membranes, leading to the formation of a fusion pore, a channel through which vesicle cargo exits into the extracellular space. In 1986, Rand and Parsegian proposed several stages to explain the nature of membrane fusion. Following stimulation, it starts with focused stress destabilization of membranes in contact, followed by the coalescence of two membrane surfaces. In the next fraction of a millisecond, restabilization of fused membranes is considered to occur to maintain the cell's integrity. This view predicted that once a fusion pore is formed, it must widen abruptly, irreversibly and fully, whereby the vesicle membrane completely integrates with and collapses into the plasma membrane (full fusion exocytosis). However, recent experimental evidence has revealed that once the fusion pore opens, it may also reversibly close (transient or kiss-and-run exocytosis). Here, we present a historical perspective on understanding the mechanisms that initiate (...)
Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy
Daniel Baumann1,2 and Rienk Offringa1,2
– [table id=351/] IDENTIFYING SUITABLE CYTOSTATIC DRUGS FOR COMBINATORIAL IMMUNOTHERAPY The main dilemma in finding combinations of cytostatic and immunostimulatory drugs that act synergistically is as follows. On the one
Hyaluronan goes to great length
Vera Gorbunova1, Masaki Takasugi1 and Andrei Seluanov1
The naked mole rat is the longest-lived rodent with the maximum lifespan of over 35 years. Naked mole rats are protected from a wide range of age-related diseases including cancer,
PRMT5 function and targeting in cancer
Hyungsoo Kim1 and Ze’ev A. Ronai1
Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapy-response. Here we discuss the function of PRMT5, a member of the nine-member PRMT family, in controlling oncogenic processes including tumor intrinsic, as well as extrinsic microenvironmental signaling pathways. We discuss PRMT5 effect on histone methylation and methylation of regulatory proteins including those involved in RNA splicing, cell cycle, cell death and metabolic signaling. In all, we highlight the importance of PRMT5 regulation and function in cancer, which provide the foundation for therapeutic modalities targeting PRMT5.
Regulation of immune checkpoint blockade efficacy in breast cancer by FIP200: A canonical-autophagy-independent function
Syn Kok Yeo1 and Jun-Lin Guan1
DISSECTING THE ROLE OF AUTOPHAGY AND AUTOPHAGY-INDEPENDENT FUNCTIONS OF FIP200 IN BREAST CANCER Although initial studies of autophagy genes in cancer implicated a tumor suppressive role, it has become apparent
Exploiting the circuit breaker cancer evolution model in human clear cell renal cell carcinoma
James J. Hsieh1 and Emily H. Cheng2,3,4
INTRODUCTION On average a human adult body encompasses fifty trillion cells (~5×1013) with a daily turnover of hundred billion cells (~1011) within which each contains two copies of ~three billion
TLR4: the fall guy in sepsis?
Joseph Menassa1, Christina Nedeva1, Corey Pollock1 and Hamsa Puthalakath1
WHOLE GENOME CRISPR SCREEN AND THE IDENTIFICATION OF Treml4 We reasoned that if immune cells undergo apoptosis during sepsis, ablation of the gene responsible for this in a sub-population should
A mutant p53/Hif1α/miR-30d axis reprograms the secretory pathway promoting the release of a prometastatic secretome
Valeria Capaci1,2, Fiamma Mantovani1 and Giannino Del Sal1,2,3
– [table id=357/] MUT-p53 AS A DRIVER OF A MALIGNANT SECRETOME p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions, and by modulating the interplay of cancer
Endocytosis in the adaptation to cellular stress
Tania López-Hernández1, Volker Haucke1,2 and Tanja Maritzen1
Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic (...)
Exocytotic fusion pore under stress
Helena Haque Chowdhury1,2 and Robert Zorec1,2
Exocytosis is a universal process of eukaryotic cells, consisting of fusion between the vesicle and the plasma membranes, leading to the formation of a fusion pore, a channel through which vesicle cargo exits into the extracellular space. In 1986, Rand and Parsegian proposed several stages to explain the nature of membrane fusion. Following stimulation, it starts with focused stress destabilization of membranes in contact, followed by the coalescence of two membrane surfaces. In the next fraction of a millisecond, restabilization of fused membranes is considered to occur to maintain the cell's integrity. This view predicted that once a fusion pore is formed, it must widen abruptly, irreversibly and fully, whereby the vesicle membrane completely integrates with and collapses into the plasma membrane (full fusion exocytosis). However, recent experimental evidence has revealed that once the fusion pore opens, it may also reversibly close (transient or kiss-and-run exocytosis). Here, we present a historical perspective on understanding the mechanisms that initiate (...)
Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy
Daniel Baumann1,2 and Rienk Offringa1,2
– [table id=351/] IDENTIFYING SUITABLE CYTOSTATIC DRUGS FOR COMBINATORIAL IMMUNOTHERAPY The main dilemma in finding combinations of cytostatic and immunostimulatory drugs that act synergistically is as follows. On the one
Hyaluronan goes to great length
Vera Gorbunova1, Masaki Takasugi1 and Andrei Seluanov1
The naked mole rat is the longest-lived rodent with the maximum lifespan of over 35 years. Naked mole rats are protected from a wide range of age-related diseases including cancer,
PRMT5 function and targeting in cancer
Hyungsoo Kim1 and Ze’ev A. Ronai1
Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapy-response. Here we discuss the function of PRMT5, a member of the nine-member PRMT family, in controlling oncogenic processes including tumor intrinsic, as well as extrinsic microenvironmental signaling pathways. We discuss PRMT5 effect on histone methylation and methylation of regulatory proteins including those involved in RNA splicing, cell cycle, cell death and metabolic signaling. In all, we highlight the importance of PRMT5 regulation and function in cancer, which provide the foundation for therapeutic modalities targeting PRMT5.
Regulation of immune checkpoint blockade efficacy in breast cancer by FIP200: A canonical-autophagy-independent function
Syn Kok Yeo1 and Jun-Lin Guan1
DISSECTING THE ROLE OF AUTOPHAGY AND AUTOPHAGY-INDEPENDENT FUNCTIONS OF FIP200 IN BREAST CANCER Although initial studies of autophagy genes in cancer implicated a tumor suppressive role, it has become apparent
Exploiting the circuit breaker cancer evolution model in human clear cell renal cell carcinoma
James J. Hsieh1 and Emily H. Cheng2,3,4
INTRODUCTION On average a human adult body encompasses fifty trillion cells (~5×1013) with a daily turnover of hundred billion cells (~1011) within which each contains two copies of ~three billion
HIF1α or mitophagy: which drives cardiomyocyte differentiation?
Beatriz Villarejo-Zori1,#, Juan Ignacio Jiménez-Loygorri1,# and Patricia Boya1
Cardiomyocytes (CMs) are the main cellular component of the heart's atria and ventricles, and their contractile capacity is the engine that drives blood flow throughout the body. The differentiation of
Copper – a novel stimulator of autophagy
Hans Zischka1,2 and Guido Kroemer3-7
In biomedicine, the transition metal copper has a Janus-faced dual role, as an essential but static cofactor of vital enzymes but also as a highly detrimental poison, if in excess.
Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses
Didier Raoult1, Alimuddin Zumla2,3, Franco Locatelli4, Giuseppe Ippolito5 and Guido Kroemer6-10,*
INTRODUCTION Infections have been limiting quality of life and longevity throughout human history. Endemic infections have been associated to a significant number of avoidable deaths and a significant increase of
ACBP is an appetite stimulator across phylogenetic barriers
Frank Madeo1,2, Nektarios Tavernarakis3,4, José M. Bravo-San Pedro5-7,# and Guido Kroemer5-10,#
Human civilization is unique with respect to the organization of our natural environment, allowing constant supply of nutrients to most individuals in developed countries, contrasting with the natural fluctuation in