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Most proteins destined for the extracellular space or various intracellular compartments must traverse the intracellular secretory pathway. The first step is the recruitment and transport of cargoes from the endoplasmic reticulum (ER) lumen to the Golgi apparatus by coat protein complex II (COPII), consisting of five core proteins. Additional ER transmembrane proteins that aid cargo recruitment are referred to as cargo receptors. Gene duplication events have resulted in multiple COPII paralogs present in the mammalian genome. Here, we review the functions of each COPII protein, human disorders associated with each paralog, and evidence for functional conservation between paralogs. We also provide a summary of current knowledge regarding two prototypical cargo receptors in mammals, LMAN1 and SURF4, and their roles in human health and disease.

Ginsburg discusses his career path and research on blood clotting and cholesterol regulation. He explores the importance of physician-scientists who can investigate diseases from both the bedside and the bench. He discusses his research on von Willebrand factor and how he used positional cloning to identify genes responsible for rare bleeding disorders. He also talks about his work on ADAMTS13, a protein involved in a blood clotting disorder called thrombotic thrombocytopenic purpura. His work on COPII components led to the identification of SURF4, a cargo receptor for PCSK9.

Santa Catalina Island, located ∼35 km off the Southern California coast, is home to the Blue Cavern Onshore State Marine Conservation Area (SMCA). Although the conservation area is recognized as both an area of special biological significance and a marine life refuge, species richness of the nearshore taxa from this location is not known. In this study, we provide a comprehensive inventory of the intertidal and subtidal marine macroalgae, plants, invertebrates, and fishes documented from 5 different reef sites inside Blue Cavern Onshore SMCA. Species richness data were compiled using scuba-based visual surveys conducted in the field, references from the primary and gray literature, research collections maintained by scholarly institutions, and field monitoring programs. The total number of marine taxa documented in this study (765 species from 17 major phylogenetic groups) represents 63% of the estimated species richness in Blue Cavern Onshore SMCA and is indicative of the high biodiversity known from this region. Specifically, the intertidal and subtidal biota reported here represent 34% and 18% of the marine taxa known from Catalina Island and the Southern California Bight, respectively. Incidences of the introduction of exotic and invasive organisms (n = 18), changes in the geographic distributions of species (n = 14), as well as marine taxa listed as species of concern, endangered, or critically endangered (n = 4), were also identified in the current inventory. Research findings presented here offer an important baseline of species richness in the California Channel Islands and will help to improve efforts by resource managers and policy makers to conserve and manage similar habitats in the coastal waters off Southern California.

Santa Catalina Island, located off the southern California coast, is home to the Blue Cavern Onshore State Marine Conservation Area (SMCA), which is recognized as a marine protected area. Here, we provide an updated species inventory of nearshore macroalgae, seagrasses, bony and cartilaginous fishes and invertebrates documented inside the Blue Cavern Onshore SMCA. Species richness data were compiled using scuba-based visual surveys conducted in the field, references from the primary and gray literature, museum records, unpublished species lists and online resources. The current checklist consists of 1091 marine species from 18 different taxonomic groups, which represents an ~43% increase in species diversity compared to the value reported previously. These data are indicative of the high biodiversity known from the Southern California Bight (SCB) region. The total number of intertidal and subtidal taxa reported represent approximately 85% and 45% of the documented macroalgae and plants, 41% and 24% invertebrates, and 62% and 20% of fishes from Catalina Island and the SCB, respectively. Among the marine taxa documented, 39 species either have undergone a geographic range shift or were introduced as the result of human activities, while another 4 species are listed as threatened, endangered or critically endangered. Research findings presented here offer an important baseline of species richness in the California Channel Islands and will help improve the efforts by resource managers and policy makers to conserve and manage similar habitats in the coastal waters off southern California.

The flow of cargo vesicles along the secretory pathway requires concerted action among various regulators. The COPII complex, assembled by the activated SAR1 GTPases on the surface of the endoplasmic reticulum, orchestrates protein interactions to package cargos and generate transport vesicles en route to the Golgi. The dynamic nature of COPII, however, hinders analysis with conventional biochemical assays. Here we apply proximity-dependent biotinylation labeling to capture the dynamics of COPII transport in cells. When SAR1B was fused with a promiscuous biotin ligase, BirA*, the fusion protein SAR1B-BirA* biotinylates and thus enables the capture of COPII machinery and cargos in a GTP-dependent manner. Biochemical and pulse–chase imaging experiments demonstrate that the COPII coat undergoes a dynamic cycle of engagement–disengagement with the transmembrane cargo receptor LMAN1/ERGIC53. LMAN1 undergoes a process of concentrative sorting by the COPII coat, via a dimeric sorting code generated by oligomerization of the cargo receptor. Similar oligomerization events have been observed with other COPII sorting signals, suggesting that dimeric/multimeric sorting codes may serve as a general mechanism to generate selectivity of cargo sorting.

Hypercholesterolemia is a causal and modifiable risk factor for atherosclerotic cardiovascular disease. A critical pathway regulating cholesterol homeostasis involves the receptor-mediated endocytosis of low-density lipoproteins into hepatocytes, mediated by the LDL receptor. We applied genome-scale CRISPR screening to query the genetic determinants of cellular LDL uptake in HuH7 cells cultured under either lipoprotein-rich or lipoprotein-starved conditions. Candidate LDL uptake regulators were validated through the synthesis and secondary screening of a customized library of gRNA at greater depth of coverage. This secondary screen yielded significantly improved performance relative to the primary genome-wide screen, with better discrimination of internal positive controls, no identification of negative controls, and improved concordance between screen hits at both the gene and gRNA level. We then applied our customized gRNA library to orthogonal screens that tested for the specificity of each candidate regulator for LDL versus transferrin endocytosis, the presence or absence of genetic epistasis with LDLR deletion, the impact of each perturbation on LDLR expression and trafficking, and the generalizability of LDL uptake modifiers across multiple cell types. These findings identified several previously unrecognized genes with putative roles in LDL uptake and suggest mechanisms for their functional interaction with LDLR.

The COVID-19 pandemic is caused by the enveloped virus SARS-CoV-2. Despite extensive investigation, the molecular mechanisms for its assembly and secretion remain largely elusive. Here, we show that SARS-CoV-2 infection induces global alterations of the host endomembrane system, including dramatic Golgi fragmentation. SARS-CoV-2 virions are enriched in the fragmented Golgi. Blocking endoplasmic reticulum (ER) to Golgi trafficking dramatically inhibits SARS-CoV-2 assembly and secretion without reducing viral genome replication. Significantly, SARS-CoV-2 infection down-regulates GRASP55 but up-regulates TGN46 protein levels. Surprisingly, GRASP55 expression reduces both viral secretion and spike number on each virion without affecting viral entry, while GRASP55 depletion displays opposite effects. In contrast, TGN46 depletion only inhibits viral secretion without affecting spike incorporation into virions. Taken together, we show that SARS-CoV-2 alters Golgi structure and function to modulate viral assembly and secretion, highlighting the Golgi as a potential therapeutic target for blocking SARS-CoV-2 infection.

PCSK9 is a secreted protein that regulates plasma cholesterol levels and cardiovascular disease risk. Prior studies suggested the presence of an ER cargo receptor that recruits PCSK9 into the secretory pathway, but its identity has remained elusive. Here, we apply a novel approach that combines proximity-dependent biotinylation and proteomics together with genome-scale CRISPR screening to identify SURF4, a homologue of the yeast cargo receptor Erv29p, as a primary mediator of PCSK9 secretion in HEK293T cells. The functional contribution of SURF4 to PCSK9 secretion was confirmed with multiple independent SURF4 -targeting sgRNAs, clonal SURF4-deficient cell lines, and functional rescue with SURF4 cDNA. SURF4 was found to localize to the early secretory pathway where it physically interacts with PCSK9. Deletion of SURF4 resulted in ER accumulation and decreased extracellular secretion of PCSK9. These findings support a model in which SURF4 functions as an ER cargo receptor mediating the efficient cellular secretion of PCSK9.

Interactions between predators and prey are often characterized by strong selection pressures that shape extreme physiological adaptations. Venom resistance in large-bodied South American opossums (Clade Didelphini) is a striking example, as these marsupials prey on venomous snakes and exhibit remarkable resistance to their venom. While resistance is well documented in Didelphini, relatively little is known about venom resistance in the smaller, more diverse members of Didelphidae, which inhabit the same regions and encounter the same predators. Moreover, resistance of opossum von Willebrand factor (VWF) to the venom C-type lectin-like proteins has not been previously studied under simulated vascular flow states. Here, we use microfluidic devices to investigate venom resistance in the small-bodied opossum, Monodelphis domestica, examining platelet adhesion and fibrin deposition in response to purified venom components. Additionally, we conduct platelet aggregometry and assays of serum protease inhibitors in the presence of venom from sympatric and allopatric vipers to examine patterns of species-specificity and adaptation. Our results show that M. domestica resists venom-induced disruptions to platelet function in the presence of platelet-disrupting venom components botrocetin and convulxin, while aspercetin disrupts platelet and fibrin function similarly in opossum and human samples. Whole blood aggregometry and serum protease inhibition showed patterns consistent with species-specific adaptation of mammals to their local snake venom. Unexpectedly, we find that M. domestica VWF requires increased shear force to elongate, a previously unknown aspect of opossum blood physiology that may contribute to venom resistance and may have relevance to human coagulopathies. Our findings demonstrate resistance under natural shear stress, and document venom resistance beyond large-bodied Didelphini, suggesting it is a widespread trait in South American marsupials.