CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
FEBS J. 2022 Dec;289(24):8037-8049. doi: 10.1111/febs.16203. Epub 2021 Oct 1.
Familial cold autoinflammatory syndrome (FCAS) is a subset of heritable autoinflammatory disorders wherein inflammatory symptoms aggravate upon exposure of the individual to subnormal temperature. In the past two decades, several mutations in various genes such as NLRP3, NLRP12, PLCG2 and NLRC4 have been identified that cause cold-triggered inflammation. However, our understanding of the mechanisms by which cells perceive subnormal temperature, and what keeps the inflammation under check until exposure to low temperature, is very limited. We hypothesise that recognition of FCAS-associated mutants as misfolded polypeptides by temperature-sensitive HSC70 (HSPA8) chaperone determines the FCAS phenotype. At 37 °C, HSC70 would interact with the mutant proteins, keeping them almost inactive, and loss of interaction at low temperature due to a conformational change in HSC70 would lead to their activation. The proposed mechanism of low temperature sensing in the context of FCAS may have wider implications for HSC70 as a cold temperature sensor in various pathological conditions where symptoms get aggravated upon exposure to low temperature.
家族性冷自身炎症综合征（FCAS）是遗传性自身炎症性疾病的一个亚类，其特征是个体暴露于亚正常温度下时炎症症状加重。在过去的二十年中，已经鉴定出 NLRP3、NLRP12、PLCγ2 和 NLRC4 等各种基因中的多种突变会导致冷触发炎症。然而，我们对于细胞如何感知亚正常温度以及在暴露于低温之前如何控制炎症的机制知之甚少。我们假设，温度敏感的 HSP70（HSPA8）伴侣蛋白将 FCAS 相关突变体识别为错误折叠的多肽，这决定了 FCAS 表型。在 37°C 时，HSC70 会与突变蛋白相互作用，使它们几乎处于非活性状态，而低温下由于 HSC70 的构象变化导致相互作用丧失，会导致它们的激活。在 FCAS 背景下低温感应的提出机制可能对 HSC70 作为各种病理条件中的冷温度传感器具有更广泛的意义，在这些条件下，症状会在暴露于低温时加重。
