scholarly journals Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1564
Author(s):  
Viraj P. Ichhaporia ◽  
Linda M. Hendershot
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Multisystem Disorder ◽  
Nucleotide Exchange Factors ◽  
Precise Understanding ◽  
Health And Disease ◽  
Client Proteins ◽  
Er Homeostasis

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.

scholarly journals Hsp70 molecular chaperones: multifunctional allosteric holding and unfolding machines

2019 ◽  
Vol 476 (11) ◽  
pp. 1653-1677 ◽  
Author(s):  
Eugenia M. Clerico ◽  
Wenli Meng ◽  
Alexandra Pozhidaeva ◽  
Karishma Bhasne ◽  
Constantine Petridis ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
The Past ◽  
Hsp70 Family ◽  
Nucleotide Exchange Factors ◽  
Client Proteins ◽  
Structural Insights ◽  
Insight Into

AbstractThe Hsp70 family of chaperones works with its co-chaperones, the nucleotide exchange factors and J-domain proteins, to facilitate a multitude of cellular functions. Central players in protein homeostasis, these jacks-of-many-trades are utilized in a variety of ways because of their ability to bind with selective promiscuity to regions of their client proteins that are exposed when the client is unfolded, either fully or partially, or visits a conformational state that exposes the binding region in a regulated manner. The key to Hsp70 functions is that their substrate binding is transient and allosterically cycles in a nucleotide-dependent fashion between high- and low-affinity states. In the past few years, structural insights into the molecular mechanism of this allosterically regulated binding have emerged and provided deep insight into the deceptively simple Hsp70 molecular machine that is so widely harnessed by nature for diverse cellular functions. In this review, these structural insights are discussed to give a picture of the current understanding of how Hsp70 chaperones work.

scholarly journals Rab35–GEFs, DENND1A and folliculin differentially regulate podocalyxin trafficking in two- and three-dimensional epithelial cell cultures

2020 ◽  
Vol 295 (11) ◽  
pp. 3652-3663
Author(s):  
Riko Kinoshita ◽  
Yuta Homma ◽  
Mitsunori Fukuda
Keyword(s):  
Cell Cultures ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Culture Conditions ◽  
Small Gtpases ◽  
Asymmetric Structure ◽  
Inositol Polyphosphate ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Polarized epithelial cells have functionally distinct apical and basolateral membranes through which they communicate with external and internal bodily environments, respectively. The establishment and maintenance of this asymmetric structure depend on polarized trafficking of specific cargos, but the precise molecular mechanism is incompletely understood. We previously showed that Rab35, a member of the Rab family small GTPases, differentially regulates the trafficking of an apical cargo, podocalyxin (PODXL), in two-dimensional (2D) and three-dimensional (3D) Madin–Darby canine kidney (MDCK) II cell cultures through specific interactions with two distinct effectors, OCRL inositol polyphosphate-5-phosphatase (OCRL) and ArfGAP with coiled-coil, ankyrin repeat and pleckstrin homology domains 2 (ACAP2), respectively. However, whether the upstream regulators of Rab35 also differ depending on the culture conditions remains completely unknown. Here, we investigated four known guanine nucleotide exchange factors (GEFs) of Rab35, namely DENN domain–containing 1A (DENND1A), DENND1B, DENND1C, and folliculin (FLCN), and demonstrate that DENND1A and FLCN exhibit distinct requirements for Rab35-dependent PODXL trafficking under the two culture conditions. In 3D cell cultures, only DENDN1A-knockout cysts exhibited the inverted localization of PODXL similar to that of Rab35-knockout cysts. Moreover, the DENN domain, harboring GEF activity toward Rab35, was required for proper PODXL trafficking to the apical membrane. By contrast, FLCN-knockdown cells specifically accumulated PODXL in actin-rich structures similar to the Rab35-knockdown cells in 2D cell cultures. Our findings indicate that two distinct functional cascades of Rab35, the FLCN-Rab35-OCRL and the DENND1A-Rab35-ACAP2 axes, regulate PODXL trafficking in 2D and 3D MDCK II cell cultures, respectively.

scholarly journals Pleiotropic Roles of Calmodulin in the Regulation of KRas and Rac1 GTPases: Functional Diversity in Health and Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 3680 ◽  
Author(s):  
Francesc Tebar ◽  
Albert Chavero ◽  
Neus Agell ◽  
Albert Lu ◽  
Carles Rentero ◽  
...  
Keyword(s):  
Biological Response ◽  
Direct Interaction ◽  
Small Gtpases ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Calmodulin Binding ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Cellular Events ◽  
And Migration

Calmodulin is a ubiquitous signalling protein that controls many biological processes due to its capacity to interact and/or regulate a large number of cellular proteins and pathways, mostly in a Ca2+-dependent manner. This complex interactome of calmodulin can have pleiotropic molecular consequences, which over the years has made it often difficult to clearly define the contribution of calmodulin in the signal output of specific pathways and overall biological response. Most relevant for this review, the ability of calmodulin to influence the spatiotemporal signalling of several small GTPases, in particular KRas and Rac1, can modulate fundamental biological outcomes such as proliferation and migration. First, direct interaction of calmodulin with these GTPases can alter their subcellular localization and activation state, induce post-translational modifications as well as their ability to interact with effectors. Second, through interaction with a set of calmodulin binding proteins (CaMBPs), calmodulin can control the capacity of several guanine nucleotide exchange factors (GEFs) to promote the switch of inactive KRas and Rac1 to an active conformation. Moreover, Rac1 is also an effector of KRas and both proteins are interconnected as highlighted by the requirement for Rac1 activation in KRas-driven tumourigenesis. In this review, we attempt to summarize the multiple layers how calmodulin can regulate KRas and Rac1 GTPases in a variety of cellular events, with biological consequences and potential for therapeutic opportunities in disease settings, such as cancer.

scholarly journals Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Angelo Giuseppe Condorelli ◽  
May El Hachem ◽  
Giovanna Zambruno ◽  
Alexander Nystrom ◽  
Eleonora Candi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Notch Pathway ◽  
Transforming Growth Factor Β1 ◽  
Notch Signalling ◽  
Skin Fibrosis ◽  
Molecular Networks ◽  
Dependent Manner ◽  
Wide Range ◽  
Health And Disease

AbstractFibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-β1, and therapeutic strategies under development.

scholarly journals SAT-144 Cooperative Mechanism of SREBP-Dependent Cholesterol Synthesis Pathway and P53 on Malignant Formation in Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Akitoshi Nakayama ◽  
Masataka Yokoyama ◽  
Hidekazu Nagano ◽  
Ikki Sakuma ◽  
Naoko Hashimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cholesterol Synthesis ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Breast Cancer Cell Lines ◽  
Mutant P53 ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Necessary And Sufficient

Abstract p53 is mutated more than half of human cancers, and mutant p53, a gain of function, can actively have functional consequences with tumorigenesis. However, its action of molecular mechanisms, particularly in vivo conditions, has not been fully are clarified. Here, we generated KO and KI (R280K) breast cancer cell lines for p53 using CRISPR/Cas9 system, and then performed a three-dimensional culture model. We found that the introduction of mutant p53 was solely able to mediate the transformation to poor architectural structure. Interestingly, our findings in statin-effect along with cholesterol synthesis pathway, especially isoprenoid dependency, revealed that this pathway is necessary and sufficient for the regulation of malignant architecture in SREBP2-dependent manner with cooperatively being controlled by mutant p53 on 3D-cultured breast cancer. Furthermore, in accordance with the malignancy progresses, SREBP2 was accumulated in nuclear and nuclear membrane portion with enhancement in malignant formation. In addition, we found that mutant p53 interacts with SREBP2, and consistently mutant p53 was associated with DHCR7 promoter in parallel with binding pattern of SREBP2. Thus, our results provide the novel insight into the mutant p53, a gain of function, and its linkage to poor architectural structure in 3D-cultured breast cancer cells via SREBP2-dependent isoprenoids regulation as potential therapeutic targets.

scholarly journals The Hsp70-Chaperone Machines in Bacteria

2021 ◽  
Vol 8 ◽  
Author(s):  
Matthias P. Mayer
Keyword(s):  
Protein Quality ◽  
Cellular Protein ◽  
Sequence Motifs ◽  
Nucleotide Exchange ◽  
Surveillance Network ◽  
Nucleotide Exchange Factors ◽  
Hsp70 Chaperone ◽  
Range Of Functions ◽  
Client Proteins ◽  
Control Circuits

The ATP-dependent Hsp70s are evolutionary conserved molecular chaperones that constitute central hubs of the cellular protein quality surveillance network. None of the other main chaperone families (Tig, GroELS, HtpG, IbpA/B, ClpB) have been assigned with a comparable range of functions. Through a multitude of functions Hsp70s are involved in many cellular control circuits for maintaining protein homeostasis and have been recognized as key factors for cell survival. Three mechanistic properties of Hsp70s are the basis for their high versatility. First, Hsp70s bind to short degenerate sequence motifs within their client proteins. Second, Hsp70 chaperones switch in a nucleotide-controlled manner between a state of low affinity for client proteins and a state of high affinity for clients. Third, Hsp70s are targeted to their clients by a large number of cochaperones of the J-domain protein (JDP) family and the lifetime of the Hsp70-client complex is regulated by nucleotide exchange factors (NEF). In this review I will discuss advances in the understanding of the molecular mechanism of the Hsp70 chaperone machinery focusing mostly on the bacterial Hsp70 DnaK and will compare the two other prokaryotic Hsp70s HscA and HscC with DnaK.

Roles of the procollagen C-propeptides in health and disease

2019 ◽  
Vol 63 (3) ◽  
pp. 313-323 ◽  
Author(s):  
David J.S. Hulmes
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Missense Mutations ◽  
Detailed Model ◽  
Morphogenetic Protein ◽  
Collagen Molecules ◽  
Health And Disease ◽  
The Stability ◽  
New Interactions

AbstractThe procollagen C-propeptides of the fibrillar collagens play key roles in the intracellular assembly of procollagen molecules from their constituent polypeptides chains, and in the extracellular assembly of collagen molecules into fibrils. Here we review recent advances in understanding the molecular mechanisms controlling C-propeptide trimerization which have revealed the importance of inter-chain disulphide bonding and a small number of charged amino acids in the stability and specificity of different types of chain association. We also show how the crystal structure of the complex between the C-propeptide trimer of procollagen III and the active fragment of procollagen C-proteinase enhancer-1 leads to a detailed model for accelerating release of the C-propeptides from procollagen by bone morphogenetic protein-1 and related proteinases. We then discuss the effects of disease-related missense mutations in the C-propeptides in relation to the sites of these mutations in the three-dimensional structure. While in general there is a good correlation between disease severity and structure-based predictions, there are notable exceptions, suggesting new interactions involving the C-propeptides yet to be characterized. Mutations affecting proteolytic release of the C-propeptides from procollagen are discussed in detail. Finally, the roles of recently discovered interaction partners for the C-propeptides are considered during fibril assembly and cross-linking.

scholarly journals TBC1D9B functions as a GTPase-activating protein for Rab11a in polarized MDCK cells

2014 ◽  
Vol 25 (23) ◽  
pp. 3779-3797 ◽  
Author(s):  
Luciana I. Gallo ◽  
Yong Liao ◽  
Wily G. Ruiz ◽  
Dennis R. Clayton ◽  
Min Li ◽  
...  
Keyword(s):  
Mdck Cells ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Limited Information ◽  
Nucleotide Exchange ◽  
Recycling Endosomes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Early Endosomes

Rab11a is a key modulator of vesicular trafficking processes, but there is limited information about the guanine nucleotide-exchange factors and GTPase-activating proteins (GAPs) that regulate its GTP-GDP cycle. We observed that in the presence of Mg2+(2.5 mM), TBC1D9B interacted via its Tre2-Bub2-Cdc16 (TBC) domain with Rab11a, Rab11b, and Rab4a in a nucleotide-dependent manner. However, only Rab11a was a substrate for TBC1D9B-stimulated GTP hydrolysis. At limiting Mg2+concentrations (<0.5 mM), Rab8a was an additional substrate for this GAP. In polarized Madin–Darby canine kidney cells, endogenous TBC1D9B colocalized with Rab11a-positive recycling endosomes but less so with EEA1-positive early endosomes, transferrin-positive recycling endosomes, or late endosomes. Overexpression of TBC1D9B, but not an inactive mutant, decreased the rate of basolateral-to-apical IgA transcytosis—a Rab11a-dependent pathway—and shRNA-mediated depletion of TBC1D9B increased the rate of this process. In contrast, TBC1D9B had no effect on two Rab11a-independent pathways—basolateral recycling of the transferrin receptor or degradation of the epidermal growth factor receptor. Finally, expression of TBC1D9B decreased the amount of active Rab11a in the cell and concomitantly disrupted the interaction between Rab11a and its effector, Sec15A. We conclude that TBC1D9B is a Rab11a GAP that regulates basolateral-to-apical transcytosis in polarized MDCK cells.

scholarly journals Human Ect2 Is an Exchange Factor for Rho Gtpases, Phosphorylated in G2/M Phases, and Involved in Cytokinesis

1999 ◽  
Vol 147 (5) ◽  
pp. 921-928 ◽  
Author(s):  
Takashi Tatsumoto ◽  
Xiaozhen Xie ◽  
Rayah Blumenthal ◽  
Isamu Okamoto ◽  
Toru Miki
Keyword(s):  
Signaling Pathways ◽  
Rho Gtpases ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Small Gtpases ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Animal Cells ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Animal cells divide into two daughter cells by the formation of an actomyosin-based contractile ring through a process called cytokinesis. Although many of the structural elements of cytokinesis have been identified, little is known about the signaling pathways and molecular mechanisms underlying this process. Here we show that the human ECT2 is involved in the regulation of cytokinesis. ECT2 catalyzes guanine nucleotide exchange on the small GTPases, RhoA, Rac1, and Cdc42. ECT2 is phosphorylated during G2 and M phases, and phosphorylation is required for its exchange activity. Unlike other known guanine nucleotide exchange factors for Rho GTPases, ECT2 exhibits nuclear localization in interphase, spreads throughout the cytoplasm in prometaphase, and is condensed in the midbody during cytokinesis. Expression of an ECT2 derivative, containing the NH2-terminal domain required for the midbody localization but lacking the COOH-terminal catalytic domain, strongly inhibits cytokinesis. Moreover, microinjection of affinity-purified anti-ECT2 antibody into interphase cells also inhibits cytokinesis. These results suggest that ECT2 is an important link between the cell cycle machinery and Rho signaling pathways involved in the regulation of cell division.

scholarly journals Microglia in Health and Disease: The Strength to Be Diverse and Reactive

2021 ◽  
Vol 15 ◽  
Author(s):  
Oihane Uriarte Huarte ◽  
Lorraine Richart ◽  
Michel Mittelbronn ◽  
Alessandro Michelucci
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Brain Diseases ◽  
Dependent Manner ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Reactive Properties

Microglia are the resident immune effector cells of the central nervous system (CNS) rapidly reacting to any perturbation in order to maintain CNS homeostasis. Although their outstanding reactive properties have been elucidated over the last decades, their heterogeneity in healthy tissue, such as across brain regions, as well as their diversity in the development and progression of brain diseases, are currently opening new avenues to understand the cellular and functional states of microglia subsets in a context-dependent manner. Here, we review the main breakthrough studies that helped in elucidating microglia heterogeneity in the healthy and diseased brain and might pave the way to critical functional screenings of the inferred cellular diversity. We suggest that unraveling the cellular and molecular mechanisms underlying specific functionalities of microglial subpopulations, which may ultimately support or harm the neuronal network in neurodegenerative diseases, or may acquire pro- or anti-tumorigenic phenotypes in brain tumors, will possibly uncover new therapeutic avenues for to date non-curable neurological disorders.

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