In most vertebrate cells, there are specialized antenna-like organelles, called primary cilia, which protrude singly from the cell body surface. They can sense extracellular cues, and retract or lengthen substantially in a short time, to participate in various physiological and pathological processes by specific signaling modules. Cell death is a fundamental biological process, which plays an essential role in the development and homeostasis of tissue and organ. Although novel cell death modes have been proposed over the last twenty years, the specific molecular mechanisms, particularly upstream signaling pathways, remain elusive. Recent studies have revealed that primary cilia can regulate cell death in response to diverse stimuli, and play a crucial role in cell death-related disorders. In this review, we highlight the current insights into the primary cilia as modulators of cell death, and discuss the ciliary signaling targeting as novel directions in the treatment of the cell death-related disorders.

Intervertebral disc (IVD) degeneration (IVDD) is the main cause of low back pain with major social and economic burdens; however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus (NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix (ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.