The lipid second messenger ceramide regulates the rate of beta cleavage of the Alzheimer's disease APP (amyloid precursor protein) by affecting the molecular stability of the beta secretase BACE1 (beta-site APP cleaving enzyme 1). Such an event is stimulated in the brain by the normal process of aging, and is under the control of the general aging programme mediated by the insulin-like growth factor 1 receptor. In the present study we report that BACE1 is acetylated on seven lysine residues of the N-terminal portion of the nascent protein. This process involves lysine acetylation in the lumen of the ER (endoplasmic reticulum) and is followed by deacetylation in the lumen of the Golgi apparatus, once the protein is fully mature. We also show that specific enzymatic activities acetylate (in the ER) and deacetylate (in the Golgi apparatus) the lysine residues. This process requires carrier-mediated translocation of acetyl-CoA into the ER lumen and is stimulated by ceramide. Site-directed mutagenesis indicates that lysine acetylation is necessary for nascent BACE1 to leave the ER and move ahead in the secretory pathway, and for the molecular stabilization of the protein.

SummaryThe transient or permanent modification of nascent proteins in the early secretory pathway is an essential cellular function that ensures correct folding and maturation of membrane and secreted proteins. We have recently described a new form of post-translational regulation of the membrane protein b-site APP cleaving enzyme 1 (BACE1) involving transient lysine acetylation in the lumen of the endoplasmic reticulum (ER). The essential components of this process are two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2, and a membrane transporter that translocates acetyl-CoA into the lumen of the ER. Here, we report the functional identification of acetyl-CoA transporter 1 (AT-1) as the ER membrane acetyl-CoA transporter. We show that AT-1 regulates the acetylation status of ER-transiting proteins, including the membrane proteins BACE1, low-density lipoprotein receptor and amyloid precursor protein (APP). Finally, we show that AT-1 is essential for cell viability as its downregulation results in widespread cell death and induction of features characteristic of autophagy.

Background: AT-1 is an ER membrane transporter that regulates the influx of acetyl-CoA into the ER lumen. Results: IRE1/XBP1 controls the induction of autophagy by regulating AT-1 expression levels and Atg9A acetylation. Conclusion: AT-1 acts downstream of the UPR to control ERAD(II).Significance: Close regulation of the acetylation status of the ER is essential for cell viability during the UPR.

We have recently identified a new form of post-translational regulation of BACE1 (b-site amyloid precursor protein (APP)-cleaving enzyme 1), a membrane protein that acts as the rate-limiting enzyme in the generation of the Alzheimer disease amyloid b-peptide (Ab). Specifically, BACE1 is transiently acetylated on seven lysine residues in the lumen of the endoplasmic reticulum/endoplasmic reticulum-Golgi intermediate compartment (ER/ERGIC). The acetylated intermediates of the nascent protein are able to reach the Golgi apparatus, whereas the non-acetylated ones are retained and degraded in a post-ER compartment. Here, we report that the serine protease PCSK9 (proprotein convertase subtilisin kexin type 9) contributes to the disposal of non-acetylated BACE1. Both overexpression and small interfering RNA-mediated downregulation of PCSK9 affected the levels of BACE1. The downregulation of PCSK9 affected the levels of the loss-of-acetylation mutants (BACE1 Ala and BACE1 Arg ) but not those of the gain-of-acetylation mutant (BACE1 Gln ). In addition, Pcsk9 À/À mice showed increased levels of BACE1 and Ab in the brain. Finally, we found that nascent low-density lipoprotein receptor, a known substrate of PCSK9, is also acetylated. Keywords: BACE1; PCSK9; lysine acetylation; Alzheimer disease EMBO reports (2008) 9, 916-922.

Hepatitis C virus (HCV) screening is recommended for patients at risk and/or born during , but screening gaps persist. This new program screens target populations and enhances care linkage for chronically HCV-infected patients. Kaiser Permanente Mid-Atlantic States created a comprehensive HCV screening pathway, supported by a HCV care coordinator. The testing pathway includes HCV antibody (Ab), automatic HCV RNA for Ab-positive patients, coinfection and liver health tests, vibration-controlled transient elastography (VCTE), and a physician referral. A total of 11 200 patients were screened; 3.25% were HCV Ab positive, and 100% of Ab-positive patients received HCV RNA testing. Of HCV Ab-positive patients, 75.9% had chronic HCV, of which 80.8% underwent VCTE. HCV diagnosis was communicated to 94% of patients, and 70.9% had HCV documented in the electronic health record. The pathway shows promise in closing gaps, including improving HCV RNA testing, communicating diagnoses, and assessing liver fibrosis. Improved testing and linkage could increase curative treatment access.

Health systems and physicians nationwide aspire to consistently and reliably apply genetic and genomic information to guide disease prevention, management, and treatment. However, clinical information, including genetics/genomics data from within and outside of the care delivery system, is expanding rapidly. Between November 2017 and April 2018, we surveyed 1502 Permanente Medical Group primary care and specialist physicians to assess the degree to which direct-to-consumer genetic test results were being presented to physicians and identify genetics educational needs among physicians (response rate 15%). Adjusted logistic regression (according to respondent characteristics) was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing responses within groups. Results showed 35% and 12% of respondents reported receiving at least one direct-to-consumer health risk genetic result (DTC-health risk) or direct-to-consumer pharmacogenomic test result (DTC-PGx), respectively, from a patient in the past year. Of those receiving at least one test result, 40% (DTC-health risk) and 39% (DTC-PGx) of physicians reported 1+ referral(s); 78% (DTC-health risk) and 42% (DTC-PGx) of referrals were to clinical genetics. In total, 85% of physicians would spend ≥2 h/year on genetics/genomics education.

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