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PICK1 Deficiency Induces Autophagy Dysfunction via Lysosomal Impairment and Amplifies Sepsis-Induced 时间:2018-10-08 09:35 来源:未知作者:admin 点击: 次 Abstract:Sepsis is a systemic inflammatory reaction caused by infection. Multiple organ failure ultimately leads to high morbidity and mortality. Unfortunately, therapies against these responses have been unsuccessful due to the insufficient underlying pathophysiological evidence. Protein interacting with C-kinase 1 (PICK1) has received considerable attention because of its important physiological functions in many tissues. However, its role in sepsis-induced acute lung injury (ALI) is unclear. In this study, we used cecal ligation and puncture (CLP) to establish a septic model and found that decreased microtubule-associated protein-1light chain 3 (LC3)-II/LC3-I in PICK1−/− septic mice was caused by autophagy dysfunction. Consistently, the transmission electron microscopy (TEM) of bone marrow-derived macrophages (BMDMs) from PICK1−/− mice showed the accumulation of autophagosomes as well. However, more serious damage was caused by PICK1 deficiency indicating that the disrupted autophagic flux was harmful to sepsis-induced ALI. We also observed that it was the impaired lysosomal function that mediated autophagic flux blockade, and the autophagy progress was relevant to PI3K-Akt-mTOR pathway. These findings will aid in the potential development of PICK1 with novel evidence of autophagy in sepsis treatment and prevention.
1. Introduction
Sepsis is a disease closely related to immune function disorders, and severe systemic inflammatory response to infection and complex clinical syndromes associated with sepsis cause death worldwide. Despite advances in treatment, sepsis still remains a life-threatening condition characterized by septic shock and organ failure complications [1]. The lung is always the first organ to be affected by sepsis. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are often the major complications of sepsis and associated with multiple organ failure [2]. As previously reported, the mortality rate of septic lung injury patients is greater than 40%, with tremendous international economic and social burden [3, 4].
Autophagy is one of the innate immune defense mechanisms against microbial challenges caused by serious sepsis [5]. Previous studies have shown that autophagy was induced in lung diseases of septic patients and animals [6]. However, the pathophysiology of these findings has not been elucidated, and whether autophagy plays a protective or harmful role is also not clarified. Autophagy is a fundamental degradation system in cells and involved in establishing an intracellular homeostasis. It is regarded as a second form of programmed cell death distinguished from apoptosis [7]. Autophagy represents an inducible response to stress including hypoxia, cigarette smoke exposure, and inflammation [8]. Dysfunctional and senescent organelles or cytosolic components are enveloped by autophagosomes, followed by transferring to lysosomes for disposal [9]. The basal autophagy serves to degrade aged and defective cellular organelles and macromolecules for reprocessing; however, when the autophagic flux was disrupted, accumulation of damaged proteins or organelles such as mitochondria would further damage the lung tissue. The complete autophagic process is dependent on normal lysosomal function, and inhibition of autophagosome degradation caused by impaired lysosome could induce autophagy dysfunction [10, 11].
Protein interacting with C-kinase 1 (PICK1) harbors a unique structure containing both BAR (Bin/Amphiphysin/Rvs) and PDZ (PSD-95/DlgA/ZO-1) domains, allowing its interaction with various transporters to regulate protein trafficking [12]. PICK1 is abundant in many tissues, especially in the brain and testis, and moderately expressed in the lungs [13]. Wang et al. have reported that PICK1 participates in ROS metabolism and is associated with impaired glutathione synthesis, with PICK1−/− mice showing increased oxidative stress accompanied by subsequent neurodegeneration [14]. Besides, PICK1 influences the progress of acrosome biogenesis, and its deficiency is accompanied by increased apoptosis [15]. PICK1 is also proved to have an anti-inflammatory role in LPS-induced acute liver injury by suppressing macrophage polarization [16]. A recent study showed that the failure of PICK1 localization to nucleus-associated acrosomic vesicles influences acrosome biogenesis in Sirtuin-1-deficient germ cells, and the progress was associated with disrupted autophagic flux [17]. But the relationship between PICK1 and autophagy is not clarified. Based on the previous evidence, we explored the relationship between PICK1 and autophagy progress.