title: Induced oligomerization targets Golgi proteins for degradation in lysosomes.
abstract: Manganese protects cells against forms of Shiga toxin by down-regulating the cycling Golgi protein GPP130. Down-regulation occurs when Mn binding causes GPP130 to oligomerize and traffic to lysosomes. To determine how GPP130 is redirected to lysosomes, we tested the role of GGA1 and clathrin, which mediate sorting in the canonical Golgi-to-lysosome pathway. GPP130 oligomerization was induced using either Mn or a self-interacting version of the FKBP domain. Inhibition of GGA1 or clathrin specifically blocked GPP130 redistribution, suggesting recognition of the aggregated GPP130 by the GGA1/clathrin-sorting complex. Unexpectedly, however, GPP130's cytoplasmic domain was not required, and redistribution also occurred after removal of GPP130 sequences needed for its normal cycling. Therefore, to test whether aggregate recognition might be a general phenomenon rather than one involving a specific GPP130 determinant, we induced homo-oligomerization of two unrelated Golgi-targeted constructs using the FKBP strategy. These were targeted to the cis- and trans-Golgi, respectively, using domains from mannosidase-1 and galactosyltransferase. Significantly, upon oligomerization, each redistributed to peripheral punctae and was degraded. This occurred in the absence of detectable UPR activation. These findings suggest the unexpected presence of quality control in the Golgi that recognizes aggregated Golgi proteins and targets them for degradation in lysosomes.
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.
authors.forename: Ritika
authors.initials: R
authors.lastname: Tewari
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.
authors.forename: Collin
authors.initials: C
authors.lastname: Bachert
authors.affiliation: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213 linstedt@andrew.cmu.edu.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Linstedt
mesh_terms: D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D055503:Protein Multimerization; D021381:Protein Transport; D059748:Proteolysis; D022621:Shiga Toxin / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C107340:GOLIM4 protein, human; D010750:Phosphoproteins; D033921:Vesicular Transport Proteins; D008345:Manganese; D022621:Shiga Toxin