Signaling via TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Previous reports demonstrated that pro-survival signaling emanates from membrane resident TNF-R1 complexes (complex I) while only internalized TNF-R1 complexes are capable for DISC formation (complex II) and thus, apoptosis induction. Internalized TNF-R1 containing endosomes undergo intracellular maturation towards lysosomes, resulting in activation and release of Cathepsin D (CtsD) into the cytoplasm. We recently revealed HSP90 as target for proteolytic cleavage by CtsD, resulting in cell death amplification.

In this study, we show that extrinsic cell death activation via TNF or TRAIL results in HSP90β degradation. Co-incubation of cells with either TNF or TRAIL in combination with the HSP90β inhibitor KUNB105 but not HSP90α selective inhibition promotes apoptosis induction. In an attempt to reveal further downstream targets of combined TNF-R1 or TRAIL-R1/-R2 activation with HSP90β inhibition, we identify HIF1α and validate its ligand:inhibitor triggered degradation.

Together, these findings suggest that selective inhibition of HSP90 isoforms together with death ligand stimulation may provide novel strategies for therapy of inflammatory diseases or cancer, in future.

通过 TNF-R1 的信号传导介导从炎症和增殖到细胞死亡的多效生物学结果。以前的报告表明，促生存信号来自膜驻留的 TNF-R1 复合物（复合物 I），而只有内化的 TNF-R1 复合物能够形成 DISC（复合物 II），从而诱导细胞凋亡。内化的含有 TNF-R1 的内体经历细胞内向溶酶体的成熟，导致组织蛋白酶 D (CtsD) 的激活和释放到细胞质中。我们最近揭示了 HSP90 作为 CtsD 蛋白水解切割的靶标，导致细胞死亡扩增。

在这项研究中，我们表明通过 TNF 或 TRAIL 激活外在细胞死亡会导致 HSP90β 降解。细胞与 TNF 或 TRAIL 与 HSP90β 抑制剂 KUNB105 联合培养，而不是 HSP90α 选择性抑制促进细胞凋亡诱导。为了揭示结合 TNF-R1 或 TRAIL-R1/-R2 激活与 HSP90β 抑制的进一步下游靶标，我们鉴定 HIF1α 并验证其配体：抑制剂触发的降解。

总之，这些发现表明，选择性抑制 HSP90 同种型以及刺激死亡配体可能在未来为炎症性疾病或癌症的治疗提供新的策略。