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Vol. 17, Issue 1, 203-212, January 2006

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Characterization of an ERAD Gene as VPS30/ATG6 Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human -1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ

Kristina B. Kruse ^*, Jeffrey L. Brodsky , and Ardythe A. McCracken ^*

^* Department of Biology, University of Nevada, Reno, NV 89557; Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260

Submitted September 3, 2004; Revised October 19, 2005; Accepted October 24, 2005
Monitoring Editor: Reid Gilmore

The Z variant of human -1 proteinase inhibitor (A1PiZ) is a substrate for endoplasmic reticulum-associated protein degradation (ERAD). To identify genes required for the degradation of this protein, A1PiZ degradation-deficient (add) yeast mutants were isolated. The defect in one of these mutants, add3, was complemented by VPS30/ATG6, a gene that encodes a component of two phosphatidylinositol 3-kinase (PtdIns 3-kinase) complexes: complex I is required for autophagy, whereas complex II is required for the carboxypeptidase Y (CPY)-to-vacuole pathway. We found that upon overexpression of A1PiZ, both PtdIns 3-kinase complexes were required for delivery of the excess A1PiZ to the vacuole. When the CPY-to-vacuole pathway was compromised, A1PiZ was secreted; however, disruption of autophagy led to an increase in aggregated A1PiZ rather than secretion. These results suggest that excess soluble A1PiZ transits the secretion pathway to the trans-Golgi network and is selectively targeted to the vacuole via the CPY-to-vacuole sorting pathway, but excess A1PiZ that forms aggregates in the endoplasmic reticulum is targeted to the vacuole via autophagy. These findings illustrate the complex nature of protein quality control in the secretion pathway and reveal multiple sites that recognize and sort both soluble and aggregated forms of aberrant or misfolded proteins.

Address correspondence to: Ardythe McCracken (mccracke{at}unr.edu).

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