Journal of Biological Chemistry

doi: 10.1016/s0021-9258(20)87246-9pmid: N/A

doi: 10.1074/jbc.p109.083311pmid: N/A

Plasmalogens are a class of ether lipids that can constitute a significant portion of the glycerophospholipid population in some tissues, notably the brain and heart. Plasmalogen synthesis goes through a 7-step reaction pathway, and now, in this Paper of the Week, Masanori Honsho and colleagues have identified the rate-limiting step. The key regulator is fatty acyl-CoA reductase 1 (Far1), the enzyme that converts fatty acyl-CoAs into fatty alcohols, which are subsequently used in the formation of ether-linked acyl bonds.

doi: 10.1016/s0021-9258(20)87245-7pmid: N/A

doi: 10.1074/jbc.p109.085779pmid: N/A

The androgen receptor (AR) is a hormone-responsive transcription factor that plays an important role in the initiation and progression of prostate cancer, likely through some interplay with the transcriptional coactivator steroid receptor coactivator-3 (SRC3, also known as AIB1). However, it's unclear how these two proteins interact as AR binds weakly to the canonical LXXLL coactivator motif present on SRC3, instead preferring an FXXLF motif (which is also present on the AR N terminus). In this Paper of the Week, though, X.

Benos, Dale J.

doi: 10.1074/jbc.r109.025072pmid: 20118247

Hypertension, or high blood pressure, is a serious health problem worldwide and is operationally defined as a resting systolic/diastolic blood pressure greater than 140/90 mm Hg. The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recently issued guidelines defining people with systolic blood pressures between 120 and 139 mm Hg and diastolic pressures between 80 and 89 mm Hg as “pre-hypertensive.” Those who fall into this category are more likely to develop frank hypertension and thus require active clinical intervention.

Wang, Zhao V.;Rothermel, Beverly A.;Hill, Joseph A.

doi: 10.1074/jbc.r109.025023pmid: 20118246

<p>In response to hypertension, the heart manifests robust hypertrophic growth, which offsets load-induced elevations in wall stress. If sustained, this hypertrophic response is a major risk factor for systolic dysfunction and heart failure. Extensive research efforts have focused on the progression from hypertrophy to failure; however, precise understanding of underlying mechanisms remains elusive. Recently, autophagy, a process of cellular cannibalization, has been implicated. Autophagy is activated during ventricular hypertrophy, serving to maintain cellular homeostasis. Excessive autophagy eliminates, however, essential cellular elements and possibly provokes cell death, which together contribute to hypertension-related heart disease.</p>

Zhang, Can;Browne, Andrew;Child, Daniel;DiVito, Jason R.;Stevenson, Jesse A.;Tanzi, Rudolph E.

doi: 10.1074/jbc.m109.079079pmid: 20097758

<p>Alzheimer disease (AD) is a devastating neurodegenerative disease with complex and strong genetic inheritance. Four genes have been established to either cause familial early onset AD (<i>APP</i>, <i>PSEN1</i>, and <i>PSEN2</i>) or to increase susceptibility for late onset AD (<i>APOE</i>). To date ∼80% of the late onset AD genetic variance remains elusive. Recently our genome-wide association screen identified four novel late onset AD candidate genes. Ataxin 1 (<i>ATXN1</i>) is one of these four AD candidate genes and has been indicated to be the disease gene for spinocerebellar ataxia type 1, which is also a neurodegenerative disease. Mounting evidence suggests that the excessive accumulation of Aβ, the proteolytic product of β-amyloid precursor protein (APP), is the primary AD pathological event. In this study, we ask whether <i>ATXN1</i> may lead to AD pathogenesis by affecting Aβ and APP processing utilizing RNA interference in a human neuronal cell model and mouse primary cortical neurons. We show that knock-down of <i>ATXN1</i> significantly increases the levels of both Aβ40 and Aβ42. This effect could be rescued with concurrent overexpression of <i>ATXN1</i>. Moreover, overexpression of <i>ATXN1</i> decreased Aβ levels. Regarding the underlying molecular mechanism, we show that the effect of <i>ATXN1</i> expression on Aβ levels is modulated via β-secretase cleavage of APP. Taken together, <i>ATXN1</i> functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-of-function mechanism by regulating β-secretase cleavage of APP and Aβ levels.</p>

Wanngren, Johanna;Frånberg, Jenny;Svensson, Annelie I.;Laudon, Hanna;Olsson, Fredrik;Winblad, Bengt;Liu, Frank;Näslund, Jan;Lundkvist, Johan;Karlström, Helena

doi: 10.1074/jbc.m109.055590pmid: 20106965

<p>γ-Secretase is an enzyme complex that mediates both Notch signaling and β-amyloid precursor protein (APP) processing, resulting in the generation of Notch intracellular domain, APP intracellular domain, and the amyloid β peptide (Aβ), the latter playing a central role in Alzheimer disease (AD). By a hitherto undefined mechanism, the activity of γ-secretase gives rise to Aβ peptides of different lengths, where Aβ42 is considered to play a particular role in AD. In this study we have examined the role of the large hydrophilic loop (amino acids 320–374, encoded by exon 10) of presenilin 1 (PS1), the catalytic subunit of γ-secretase, for γ-secretase complex formation and activity on Notch and APP processing. Deletion of exon 10 resulted in impaired PS1 endoproteolysis, γ-secretase complex formation, and had a differential effect on Aβ-peptide production. Although the production of Aβ38, Aβ39, and Aβ40 was severely impaired, the effect on Aβ42 was affected to a lesser extent, implying that the production of the AD-related Aβ42 peptide is separate from the production of the Aβ38, Aβ39, and Aβ40 peptides. Interestingly, formation of the intracellular domains of both APP and Notch was intact, implying a differential cleavage activity between the ϵ/S3 and γ sites. The most C-terminal amino acids of the hydrophilic loop were important for regulating APP processing. In summary, the large hydrophilic loop of PS1 appears to differentially regulate the relative production of different Aβ peptides without affecting Notch processing, two parameters of significance when considering γ-secretase as a target for pharmaceutical intervention in AD.</p>

Honsho, Masanori;Asaoku, Shunsuke;Fujiki, Yukio

doi: 10.1074/jbc.m109.083311pmid: 20071337

<p>Plasmalogens are a major subclass of ethanolamine and choline glycerophospholipids in which a long chain fatty alcohol is attached at the <i>sn</i>-1 position through a vinyl ether bond. This ether-linked alkyl bond is formed in peroxisomes by replacement of a fatty acyl chain in the intermediate 1-acyl-dihydroxyacetone phosphate with a fatty alcohol in a reaction catalyzed by alkyl dihydroxyacetone phosphate synthase. Here, we demonstrate that the enzyme fatty acyl-CoA reductase 1 (Far1) supplies the fatty alcohols used in the formation of ether-linked alkyl bonds. Far1 activity is elevated in plasmalogen-deficient cells, and conversely, the levels of this enzyme are restored to normal upon plasmalogen supplementation. Down-regulation of Far1 activity in response to plasmalogens is achieved by increasing the rate of degradation of peroxisomal Far1 protein. Supplementation of normal cells with ethanolamine and 1-<i>O</i>-hexadecylglycerol, which are intermediates in plasmalogen biosynthesis, accelerates degradation of Far1. Taken together, our results indicate that ether lipid biosynthesis in mammalian cells is regulated by a negative feedback mechanism that senses cellular plasmalogen levels and appropriately increases or decreases Far1.</p>

Fernández-Messina, Lola;Ashiru, Omodele;Boutet, Philippe;Agüera-González, Sonia;Skepper, Jeremy N.;Reyburn, Hugh T.;Valés-Gómez, Mar

doi: 10.1074/jbc.m109.045906pmid: 20080967

<p>Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.</p>