SIRT1/PGC-1: a neuroprotective axis?

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.     

HIV-1: Is Nef a PAK animal?

HIV-1 Nef is clearly essential for efficient viral replication in vivo, but it has been difficult to determine why. Recent evidence that Nef specifically activates a PAK-dependent signaling cascade may be the first step in defining the mechanism of action of this enigmatic viral protein.     

Methylation: a regulator of HIV-1 replication?

Pakistan, the second most populous Muslim nation in the world, has started to finally experience and confront the HIV/AIDS epidemic. The country had been relatively safe from any indigenous HIV cases for around two decades, with most of the infections being attributable to deported HIV positive migrants from the Gulf States. However, the virus finally seems to have found a home-base, as evidenced by the recent HIV outbreaks among the injection drug user community. Extremely high-risk behavior has also been documented among Hijras (sex workers) and long-distance truck drivers. The weak government response coupled with the extremely distressing social demographics of this South-Asian republic also helps to compound the problem. The time is ripe now to prepare in advance, to take the appropriate measures to curtail further spread of the disease. If this opportunity is not utilized right now, little if at all could be done later.     

Blood-bank testing for infectious diseases: how safe is blood transfusion?

Remarkable progress has been made in transfusion safety from infection over the past three decades. Donor deferrals for at-risk behaviors, the introduction of more-sensitive viral-screening assays and the recent introduction of nucleic-acid amplification technology have nearly eliminated transmission of HIV and hepatitis C virus (HCV) by blood transfusion in North America. Nevertheless, risks of other infectious agents for which such robust screening tools have not been developed, such as bacteria and parasites, still remain. As a result of these successes, the non-infectious risks such as misidentification of patients and inadequate and inappropriate transfusion have become the primary sources of transfusion risk.     

Helicobacter pylori gastritis: a Th1 mediated disease?

Helicobacter pylori is now considered to be the main cause for most stomach diseases including ulcer, MALT lymphoma, adenocarcinoma and gastritis. The infection with this bacterium is chronic despite a local and systemic immune response towards it. Among the cellular infiltrate that arises during H. pylori-mediated gastritis, there is a considerable frequency of CD4+ Th1 cells producing IFNgamma, but not of Th2 cells producing IL-4. Since IFNgamma may induce binding of H. pylori to gastric epithelial cells followed by apoptosis of these cells, one may speculate that H. pylori-mediated diseases are in part autoimmune diseases initiated by H. pylori-specific Th1 cells infiltrating the gastric mucosa. Recent support for this hypothesis comes from an animal model in which mice are infected with H. pylori and display strongly reduced gastritis in the absence of IFNgamma.     

Unraveling ICAP-1 function: Toward a new direction?

Cell adhesion to either the extracellular matrix (ECM) or to neighboring cells is of critical importance during both physiological and pathological situations. Integrins are a large family of cell adhesion receptors composed of two non-covalently linked alpha and beta subunits. They have a well-identified dual function of mediating both firm adhesion and signaling. The short cytoplasmic domain of integrin can interact with cytoplasmic proteins that are either shared by several different integrins or specific for one type of integrin. Integrin cytoplasmic domain-associated protein-1 (ICAP-1) is a small cytoplasmic protein that specifically interacts with the beta1 integrin subunit. In this review we will discuss recent findings on ICAP-1, not only at the structural and functional level, but also its possible interconnection in other signaling pathways such as those that control cell proliferation.     

HMGB1: a smoking gun in lupus nephritis?

High-mobility group box 1 protein (HMGB1) is a prototypic alarmin that is released from activated and dying cells. Because of its proinflammatory activities, HMGB1 could mediate key events in the pathogenesis of systemic lupus erythematosus, a possibility supported by elevations of HMGB1 in patient blood and increased expression in renal biopsies. The biology of HMGB1 is complicated, however, and its activity is dependent on redox state as well as binding to other molecules such as cytokines. Defining more precisely the role of HMGB1 in lupus will require treatment studies to block the activity of this alarmin in animal models and ultimately patients.A smoking gun is probably the most dramatic and iconic evidence of a crime. The concept of the smoking gun originated in a Sherlock Holmes story and then languished until it exploded into awareness during the impeachment hearings of Richard Nixon. As now understood, a smoking gun is an incontrovertible piece of evidence to establish a crime and even identify the perpetrator. This is especially true if the gun, sulfurous fumes streaming from the barrel, resides in the hand of a suspect, the murder victim bleeding nearby.In rheumatology as in all of medicine, investigators are forever searching for the smoking guns of pathogenesis. The identification of such guns, especially when found at the crime scene (such as a kidney biopsy), can delineate the mechanism of tissue injury as well as suggest new targets of therapy. Smoking guns in medicine can be very elusive, however, and cold cases abound. Assembling a case beyond a reasonable doubt can require a multitude of in vitro and in vivo studies, including treatment trials in animal models as well as patients.In the previous issue of Arthritis Research & Therapy, Zickert and colleagues [1] provided important new evidence implicating high-mobility group box 1 protein (HMGB1) as a mediator of lupus nephritis, and the enhanced expression of HMGB1 is perhaps a smoking gun in the pathogenesis of a very complicated disease. As the data presented indicate, levels of HMGB1 are elevated in the blood of patients with lupus nephritis; furthermore, renal biopsies showed increased HMGB1 expression in the mesangium and endothelium. The elevations of HMGB1 in blood occurred in patients with different histopathological forms of lupus nephritis but, interestingly, did not vary much over time or with treatment [1].These observations are important in view of the biological properties of HMGB1. HMGB1 is a prototype alarmin and, indeed, the prime example of this class of immune mediator. In other terminology, HMGB1 is a DAMP (damage-associated molecular pattern). The immune activities of HMGB1 are perhaps surprising since HMGB1 is a nuclear molecule ubiquitously expressed in cells. In its usual location, HMGB1 can bind DNA as an architectural element for chromatin structure; once released from cells, however, HMGB1 acquires a new identity and displays potent and varied immunological activities. This release can occur during immune cell activation as well as cell death, whether apoptosis or necrosis [2].Along with other studies on systemic lupus erythematosus [3-5], the evidence for a central role of HMGB1 in lupus pathogenesis is strong but nevertheless circumstantial. One of the difficulties in making the case watertight concerns the complex biology of HMGB1. While HMGB1 has immunological activity, the extent of such activity varies significantly depending on its structure, including the redox state of cysteine (C) residues at positions 23, 45, and 106. With pure HMGB1, activity requires a C106 thiol and a C23-45 disulfide bond to induce activation of nuclear factor-kappa-B. With these modifications, HMGB1 can bind to Toll-like receptor 4 (TLR4) to stimulate responses but the oxidized form lacks such activity [6,7]. Thus, the finding of HMGB1 in the blood or tissue does not prove that it is functionally active.A further complexity concerns the manner in which HMGB1 stimulates inflammation. While active by itself depending on redox state, HMGB1 can also function in concert with cytokines such as interleukin-1 (IL-1). These complexes can stimulate responses through the cytokine receptor to dramatically boost immunostimulatory activity [8,9]. Similarly, HMGB1 can form complexes with PAMPs (pathogen-associated molecular patterns) such as lipopolysaccharide or CpG DNA to act via a TLR. Thus, the finding of high levels of HMGB1 in the blood or tissue is the beginning, not the end, of the story. In the absence of a partner in crime such as IL-1 or lipopolysaccharide, the effect of this molecule may be limited depending on the status of the cysteines [10].As is now recognized, HMGB1 emanates from cells during activation, necrosis, and apoptosis. Whereas HMGB1 from activated and necrotic cells has alarmin activity, HMGB1 released during apoptosis may lack such activity because of oxidation [7]. Since tissue injury (for example, ischemia) can lead to apoptosis and therefore HMGB1 release, the presence of extracellular HMGB1 may denote the effects of injury rather than establish the cause. In this regard, HMGB1 can be a component of immune complexes in lupus, likely reflecting its interaction with DNA that emerges from dead or dying cells [4,5]. The role of HMGB1 in nephritis as opposed to dendritic cell activation is not yet clear, although, as shown in the current study, the finding of HMGB1 in the mesangium may signify immune deposition; in this case, the activation of the complement system, rather than any direct effect of HMGB1 itself, may be the key event in inciting nephritis.HMGB1 has generated great interest as a new target of immununosuppressive therapy since, in animal models of shock and arthritis, blocking the action of HMGB1 can be strikingly beneficial [2]. Such studies are awaited in lupus. Only then will it be possible to know whether the HMGB1 gun in lupus nephritis is smoking or just smoldering.     

LKB1: a sweet side to Peutz-Jeghers syndrome?

The recent discovery that the tumour suppressor LKB1 is an upstream kinase in the AMP-activated protein kinase (AMPK) cascade provided a molecular link between energy metabolism and cancer. A recent study by Shaw and colleagues elucidated the role of LKB1 in type 2 diabetes. Deletion of the gene encoding LKB1 in the liver leads to marked hyperglycaemia as a consequence of increased gluconeogenic gene expression and hepatic glucose output. Importantly, the absence of LKB1 in the liver abolishes the effect of lowering glucose level caused by metformin, a drug that is widely used for the treatment of type 2 diabetes. These findings should help solve the mystery surrounding the function of metformin, which has lasted for >30 years.     

Vipp1: a very important protein in plastids?!

As a key feature in oxygenic photosynthesis, thylakoid membranes play an essential role in the physiology of plants, algae, and cyanobacteria. Despite their importance in the process of oxygenic photosynthesis, their biogenesis has remained a mystery to the present day. A decade ago, vesicle-inducing protein in plastids 1 (Vipp1) was described to be involved in thylakoid membrane formation in chloroplasts and cyanobacteria. Most follow-up studies clearly linked Vipp1 to membranes and Vipp1 interactions as well as the defects observed after Vipp1 depletion in chloroplasts and cyanobacteria indicate that Vipp1 directly binds to membranes, locally stabilizes bilayer structures, and thereby retains membrane integrity. Here current knowledge about the structure and function of Vipp1 is summarized with a special focus on its relationship to the bacterial phage shock protein A (PspA), as both proteins share a common origin and appear to have retained many similarities in structure and function.     

The insulin receptor substrate-1: a biomarker for cancer?

This review focuses on IRS-1 and the evidence of its role in cell transformation. The literature strongly suggests that IRS-1 should be considered a biomaker for cancers susceptible to IGF-IR targeting. In addition, I would like to propose that IRS-1 may have a more general role in cancer, and could be considered as a protein having the opposite effect of tumor suppressors, a sort of anti-p53 molecule.     

The human Cas1 protein: a sialic acid-specific O-acetyltransferase?

Sialic acids are important sugars at the reducing end of glycoproteins and glycolipids. They are among many other functions involved in cell-cell interactions, host-pathogen recognition and the regulation of serum half-life of glycoproteins. An important modification of sialic acids is O-acetylation, which can alter or mask the biological properties of the parent sialic acid molecule. The nature of mammalian sialate-O-acetyltransferases (EC 2.3.1.45) involved in their biosynthesis is still unknown. We have identified the human CasD1 (capsule structure1 domain containing 1) gene as a candidate to encode the elusive enzyme. The human CasD1 gene encodes a protein with a serine-glycine-asparagine-histidine hydrolase domain and a hydrophobic transmembrane domain. Expression of the Cas1 protein tagged with enhanced green fluorescent protein in mammalian and insect cells directed the protein to the medial and trans-cisternae of the Golgi. Overexpression of the Cas1 protein in combination with α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (GD3 synthase) resulted in an up to 40% increased biosynthesis of 7-O-acetylated ganglioside GD3. By quantitative real-time polymerase chain reaction, we found up to 5-fold increase in CasD1 mRNA in tumor cells overexpressing O-Ac-GD3. CasD1-specific small interfering RNA reduced O-acetylation in tumor cells. These results suggest that the human Cas1 protein is directly involved in O-acetylation of α2-8-linked sialic acids.