BAG family proteins are regulatory co-chaperones for heat shock protein (Hsp) 70. Hsp70 facilitates the removal of injured proteins by ubiquitin-mediated proteasomal degradation. This process can be driven by geldanamycin, an irreversible blocker of Hsp90. We hypothesize that CAIR-1/BAG-3 inhibits Hsp-mediated proteasomal degradation. Human breast cancer cells were engineered to overexpress either full-length CAIR-1 (FL), which binds Hsp70, or a BAG domain-deletion mutant (dBAG) that cannot bind Hsp70. FL overexpression prevented geldanamycin-mediated loss of total and phospho-Akt and other Hsp client proteins. dBAG provided no protection, indicating a requirement for Hsp70 binding. Ubiquitinated Akt accumulated in FL-expressing cells, mimicking the effect of lactacystin proteasomal inhibition, indicating that CAIR-1 inhibits proteasomal degradation distal to protein ubiquitination in a BAG domain-dependent manner. Protein protection in FL cells was generalizable to downstream Akt targets, GSK3␤, P70S6 kinase, CREB, and other Hsp client proteins, including Raf-1, cyclin-dependent kinase 4, and epidermal growth factor receptor. These findings suggest that Hsp70 is a chaperone driving a multiprotein degradation complex and that the inhibitory co-chaperone CAIR-1 functions distal to client ubiquitination. Furthermore, poly-ubiquitination is not sufficient for efficient proteasomal targeting of Hsp client proteins.

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Dura-based marginal zone lymphomas represent an uncommon group of low-grade B-cell neoplasms, and literature regarding the clinical, histological and genetic profile of these tumors in the context of the newly described IgG4-related entities is lacking. We analyzed 32 dura-based marginal zone lymphomas identified in 27 females and 5 males ranging in age from 33-82 years (median 50). Morphologic examination, immunohistochemical studies and PCR for B-cell clonality were carried out in all cases. In addition, IgG4 immunohistochemistry and cytogenetic studies (either by FISH or RT-PCR) were carried out in 20 (18 primary dural; 2 with associated extradural disease) and 9 cases, respectively. Clinically, most cases presented radiologically as dura-based masses, mimicking meningioma. Histologically, the majority exhibited plasmacytoid differentiation, and were clonal either by PCR or immunohistochemical light chain analysis (28 out of 32). In the subset tested for IgG4, 6 of 18 primary dural marginal zone lymphoma (including one epidural tumor) showed numerous IgG4-positive plasma cells; all 6 were light chain restricted and clonal by PCR in 5 of 6 tested cases. Three IgG4-positive marginal zone lymphomas tested for cytogenetics did not show any cytogenetic aberrations. Across all cases, FISH and RT-PCR identified abnormalities in three out of nine cases (trisomies 3 and 18; trisomies 3 and 1; trisomy 18) without any extranodal marginal zone lymphoma specific translocations. Regardless of the treatment modality, 16 of 17 patients with follow-up are alive without evidence of disease over a period of 4-124 months (median 19.5). The expression of IgG4 in light-chain-restricted clonal plasma cells of a significant subset of dural marginal zone lymphomas, including one in an epidural location, is a novel finding and points to distinctive biology. Cytogenetic aberrations are present only in a minority of dural marginal zone lymphomas.