Frequency of Complete Atrioventricular Block Complicating ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention.

OBJECTIVES: ST-segment elevation myocardial infarction (STEMI) can be associated with many conduction disturbances including complete atrioventricular block (CAVB). CAVB complicating STEMI resulted in an increased mortality before the modern era of primary percutaneous coronary intervention (PCI). The aim of this study was to ascertain the rate and risk factors for CAVB in STEMI patients undergoing rapid reperfusion with PCI. METHODS: We analyzed 223 patients presenting with STEMI. Patient characteristics, procedural characteristics, and in-hospital data were compared between patients with and without CAVB. RESULTS: Out of 223 patients, 174 underwent PCI; the majority (87%) was African-American. CAVB was present in 8 patients (4.6%), and 6 of them had RCA occlusion. Independent predictors of CAVB included diabetes mellitus, female gender, lower systolic and diastolic blood pressure, and inferior-lateral/lateral STEMI. Ten patients (5.7%) required temporary pacing at presentation; only 1 patient required permanent pacing before discharge. No patient with anterior STEMI developed CAVB. CONCLUSIONS: The incidence and in-hospital mortality rate of CAVB in patients with STEMI who underwent primary PCI was reduced when compared to data from the thrombolytic era. This may be due to faster flow recovery in the infarct-related artery achieved with PCI.

GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation.

COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.

Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB.

BACKGROUND: Sorting ubiquitinated epidermal growth factor receptor (EGFR) to the intralumenal vesicles of the multivesicular body requires the coordinated action of several ESCRT complexes. A central question is how EGFR transits vectorially from early, ubiquitin-binding ESCRTs to the final complex, ESCRT-III, such that cargo sequestration is coupled with intralumenal vesicle formation. RESULTS: We show that the ESCRT accessory protein HD-PTP/PTPN23 associates with EGFR and combines with the deubiquitinating enzyme UBPY/USP8 to transfer EGFR from ESCRT-0 to ESCRT-III and drive EGFR sorting to intralumenal vesicles. HD-PTP binds ESCRT-0 via two interactions with the STAM2 subunit. First, the HD-PTP Bro1 domain binds the core domain of STAM2. This is competed by the ESCRT-III subunit CHMP4B, which binds an overlapping site on HD-PTP Bro1. Second, a proline-rich peptide in HD-PTP binds the SH3 domain of STAM2. Similar proline-rich peptides on UBPY also bind STAM2 SH3 to facilitate EGFR deubiquitination. Hence, locally recruited UBPY would be expected to compete with HD-PTP for STAM2 binding at this second site. Indeed, we show that HD-PTP recruits UBPY to EGFR. Association of UBPY with HD-PTP involves UBPY interacting with HD-PTP-bound CHMP4B, as well as additional interaction(s) between UBPY and HD-PTP. CONCLUSIONS: This study identifies HD-PTP as a central coordinator of the ESCRT pathway for EGFR. Based on these studies, we propose a model whereby the concerted recruitment of CHMP4B and UBPY to HD-PTP and the engagement of UBPY by STAM2 displaces ESCRT-0 from HD-PTP, deubiquitinates EGFR, and releases ESCRT-0 from cargo in favor of ESCRT-III.