Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.

Protein aggregation is a hallmark of neurodegeneration. Here, we find that Huntington's disease-related HTT-polyQ aggregation induces a cellular proteotoxic stress response, while ALS-related mutant FUS (mutFUS) aggregation leads to deteriorated proteostasis. Further exploring chaperone function as potential modifiers of pathological aggregation in these contexts, we reveal divergent effects of naturally-occurring chaperone isoforms on different aggregate types. We identify a complex of the full-length (FL) DNAJB14 and DNAJB12, that substantially protects from mutFUS aggregation, in an HSP70-dependent manner. Their naturally-occurring short isoforms, however, do not form a complex, and lose their ability to preclude mutFUS aggregation. In contrast, DNAJB12-short alleviates, while DNAJB12-FL aggravates, HTT-polyQ aggregation. DNAJB14-FL expression increases the mobility of mutFUS aggregates, and restores the deteriorated proteostasis in mutFUS aggregate-containing cells and primary neurons. Our results highlight a maladaptive cellular response to pathological aggregation, and reveal a layer of chaperone network complexity conferred by DNAJ isoforms, in regulation of different aggregate types.

Cellular proteostasis decline in human senescence.

Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

Human cytomegalovirus infection enhances NF-κB/p65 signaling in inflammatory breast cancer patients.

Human Cytomegalovirus (HCMV) is an endemic herpes virus that re-emerges in cancer patients enhancing oncogenic potential. Recent studies have shown that HCMV infection is associated with certain types of cancer morbidity such as glioblastoma. Although HCMV has been detected in breast cancer tissues, its role, if any, in the etiology of specific forms of breast cancer has not been investigated. In the present study we investigated the presence of HCMV infection in inflammatory breast cancer (IBC), a rapidly progressing form of breast cancer characterized by specific molecular signature. We screened for anti-CMV IgG antibodies in peripheral blood of 49 non-IBC invasive ductal carcinoma (IDC) and 28 IBC patients. In addition, we screened for HCMV-DNA in postsurgical cancer and non-cancer breast tissues of non-IBC and IBC patients. We also tested whether HCMV infection can modulate the expression and activation of transcriptional factor NF-κB/p65, a hallmark of IBC. Our results reveal that IBC patients are characterized by a statistically significant increase in HCMV IgG antibody titers compared to non-IBC patients. HCMV-DNA was significantly detected in cancer tissues than in the adjacent non-carcinoma tissues of IBC and IDC, and IBC cancer tissues were significantly more infected with HCMV-DNA compared to IDC. Further, HCMV sequence analysis detected different HCMV strains in IBC patients tissues, but not in the IDC specimens. Moreover, HCMV-infected IBC cancer tissues were found to be enhanced in NF-κB/p65 signaling compared to non-IBC patients. The present results demonstrated a correlation between HCMV infection and IBC. Etiology and causality of HCMV infection with IBC now needs to be rigorously examined.