Mutations in the nuclear envelope proteins lamins A and C cause a broad variety of human diseases, including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. Cells lacking lamins A and C have reduced nuclear stiffness and increased nuclear fragility, leading to increased cell death under mechanical strain and suggesting a potential mechanism for disease. Here, we investigated the contribution of major lamin subtypes (lamins A, C, and B1) to nuclear mechanics by analyzing nuclear shape, nuclear dynamics over time, nuclear deformations under strain, and cell viability under prolonged mechanical stimulation in cells lacking both lamins A and C, cells lacking only lamin A (i.e."lamin C-only" cells), cells lacking wild-type lamin B1, and wild-type cells. Lamin A/C-deficient cells exhibited increased numbers of misshapen nuclei and had severely reduced nuclear stiffness and decreased cell viability under strain. Lamin C-only cells had slightly abnormal nuclear shape and mildly reduced nuclear stiffness but no decrease in cell viability under strain. Interestingly, lamin B1-deficient cells exhibited normal nuclear mechanics despite having a significantly increased frequency of nuclear blebs. Our study indicates that lamins A and C are important contributors to the mechanical stiffness of nuclei, whereas lamin B1 contributes to nuclear integrity but not stiffness.Lamins are type V intermediate filament proteins that form the nuclear lamina, a filamentous network underlying the inner nuclear membrane of eukaryotic cells. Lamins form stable structures in the nuclear lamina and the nucleoplasm, determine nuclear shape and size, resist nuclear deformation, and position nuclear pore complexes (reviewed in Refs. 1-3). In addition, lamins recruit and anchor, either directly or indirectly, several nuclear envelope proteins (e.g. nesprin-1␣, emerin, and the lamin B receptor) to the inner nuclear membrane (3).Mammalian cells express two types of lamins, the A and B types. Both share a common structural organization: a globular N-terminal domain separated from a larger C-terminal globular domain by a central helical rod domain that allows lamins to form parallel coiled-coil dimers, which in turn assemble into stable strings and higher order networks. Lamins A and C, the major A-type lamins, are alternatively spliced isoforms of a single gene, LMNA. The expression of A-type lamins is developmentally regulated, beginning midway through embryonic development (4). A-type lamins are expressed in most but not all differentiated cells (5). B-type lamins (lamins B1 and B2) are encoded by separate genes, LMNB1 and LMNB2, respectively (6). Unlike A-type lamins, B-type lamins are expressed in all cells and throughout development (7,8), although it is not clear if they are always coexpressed at equivalent levels in the same cell.

The other-race effect (ORE), or the finding that same-race faces are better recognized than other-race faces, is one of the best replicated phenomena in face recognition. The current article reviews existing evidence and theory and proposes a new theoretical framework for the ORE, which argues that the effect results from a confluence of social categorization, motivated individuation, and perceptual experience. This categorization-individuation model offers not only a parsimonious account of both classic and recent evidence for category-based biases in face recognition but also links the ORE to broader evidence and theory in social cognition and face perception. Finally, the categorization-individuation model makes a series of novel predictions for how the ORE can be exacerbated, attenuated, or even eliminated via perceptual and motivational processes, both by improving other-race recognition and by reducing same-race recognition. The authors propose that this new model for the ORE also leads to applied interventions that differ sharply from other theories of the ORE, while simultaneously providing an integrative theoretical framework for future research on the ORE.

The triglycerides in chylomicrons are hydrolyzed by lipoprotein lipase (LpL) along the luminal surface of the capillaries. However, the endothelial cell molecule that facilitates chylomicron processing by LpL has not yet been defined. Here, we show that glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) plays a critical role in the lipolytic processing of chylomicrons. Gpihbp1-deficient mice exhibit a striking accumulation of chylomicrons in the plasma, even on a low-fat diet, resulting in milky plasma and plasma triglyceride levels as high as 5000 mg/dl. Normally, Gpihbp1 is expressed highly in heart and adipose tissue, the same tissues that express high levels of LpL. In these tissues, GPIHBP1 is located on the luminal face of the capillary endothelium. Expression of GPIHBP1 in cultured cells confers the ability to bind both LpL and chylomicrons. These studies strongly suggest that GPIHBP1 is an important platform for the LpL-mediated processing of chylomicrons in capillaries.

Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum. Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24 ؊/؊ ) have indicated a role for Zmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologic consequences of Zmpste24 deficiency in mice. Zmpste24 ؊/؊ mice gain weight slowly, appear malnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes are significantly reduced in Zmpste24 ؊/؊ mice. Zmpste24 ؊/؊ mice also manifested muscle weakness in the lower and upper extremities, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24 ؊/؊ mice can be reasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a broader role for Zmpste24 in mammalian biology.metalloproteinase ͉ knockout mice ͉ brittle bones ͉ CAAX motif T he mammalian zinc metalloproteinase Zmpste24 has attracted attention because it shares a high degree of sequence identity with Ste24p, a Saccharomyces cerevisiae enzyme required for the maturation of the farnesylated mating pheromone a-factor (1-3). Ste24p plays two distinct roles in a-factor biogenesis (2, 4). First, it acts as a CAAX endoprotease, clipping off the C-terminal three amino acids from the protein (i.e., the ϪAAX of the CAAX motif) (3). Release of the ϪAAX from a-factor can also be mediated by Rce1p, the CAAX endoprotease involved in Ras processing (3). The removal of the ϪAAX exposes a carboxyl-terminal farnesylcysteine, which is methylated by Ste14p (5). Second, Ste24p clips the amino-terminal extension of a-factor, rendering it susceptible to a final endoproteolytic cleavage by Axl1p or Ste23p (6). Aside from a-factor, no other substrates for Ste24p have been identified, but other substrates likely exist because genetic screens in yeast have demonstrated that STE24 mutations can reverse the topological orientation of membrane proteins (7) and can affect the viability of yeast with mutations in genes encoding actin cytoskeleton proteins (8).Zmpste24 faithfully carries out both of Ste24p's processing steps in a-factor biogenesis and thus is a bona fide Ste24p ortholog (2, 9). Although it would be tempting to speculate that Zmpste24 processes an ''a-factor-like'' peptide in mammals, no a-factor ortholog has yet been identified. We have previously speculated that prelamin A (a precursor to lamin A, a component of the nuclear lamina) might be a Zmpste24 substrate (2, 6) because prelamin A (like yeast a-factor) is a farnesylated CAAX protein that undergoes more than one proteolytic processing step (10). After the removal of the C-terminal ϪAAX, an additional 15 res...

Defects in the endosomal-lysosomal pathway have been implicated in a number of neurodegenerative disorders. A key step in the endocytic regulation of transmembrane proteins occurs in a subset of late-endosomal compartments known as multivesicular bodies (MVBs), whose formation is controlled by endosomal sorting complex required for transport (ESCRT). The roles of ESCRT in dendritic maintenance and neurodegeneration remain unknown. Here, we show that mSnf7-2, a key component of ESCRT-III, is highly expressed in most mammalian neurons. Loss of mSnf7-2 in mature cortical neurons caused retraction of dendrites and neuronal cell loss. mSnf7-2 binds to CHMP2B, another ESCRT-III subunit, in which a rare dominant mutation is associated with frontotemporal dementia linked to chromosome 3 (FTD3). Ectopic expression of the mutant protein CHMP2B(Intron5) also caused dendritic retraction prior to neurodegeneration. CHMP2B(Intron5) was associated more avidly than CHMP2B(WT) with mSnf7-2, resulting in sequestration of mSnf7-2 in ubiquitin-positive late-endosomal vesicles in cortical neurons. Moreover, loss of mSnf7-2 or CHMP2B(Intron5) expression caused the accumulation of autophagosomes in cortical neurons and flies. These findings indicate that ESCRT-III dysfunction is associated with the autophagy pathway, suggesting a novel neurodegeneration mechanism that may have important implications for understanding FTD and other age-dependent neurodegenerative diseases.