巨自噬/自噬是一种严格调控的细胞过程，是稳态和先天免疫不可或缺的一部分。因此，自噬失调与癌症、神经退行性疾病和传染病有关。虽然促进自噬的许多因素已经被表征，但防止过度自噬的关键机制尚不清楚。在这里，我们将 CSNK2/CK2（酪蛋白激酶 2）确定为自噬的负调节因子。 CSNK2 活性的药理学抑制或 siRNA 介导的 CSNK2 消耗增加了细胞系和原代人肺细胞的基础自噬通量。反之亦然，CSNK2 的异位表达减少了自噬通量。从机制上讲，CSNK2 与包含 FLN（丝蛋白）-NHL 结构域的三联基序 (TRIM) 家族成员 TRIM2、TRIM3 和 TRIM71 相互作用。我们的数据表明，CSNK2 招募到 TRIM3 C 端 NHL 结构域导致 CSNK2 在丝氨酸 661 处强烈磷酸化。 TRIM3 的磷酸化缺陷突变体无法减少自噬体数量，表明 TRIM 介导的自噬抑制需要 CSNK2 的磷酸化。所有三种 TRIM 通过促进 ULK1 丝氨酸 757 磷酸化来促进 ULK1-BECN1 自噬起始复合物的失活。抑制 CSNK2 可促进甲型流感病毒 (IAV) 和麻疹病毒 (MeV) 感染时的自噬。与此相符，靶向 CSNK2 或消除 TRIM2、TRIM3 或 TRIM71 增强了 IAV、MeV 和人类免疫缺陷病毒 1 (HIV-1) 的自噬依赖性限制。因此，我们的结果确定 CSNK2-TRIM2、-TRIM3、-TRIM71 轴是限制自噬的关键调控途径。靶向该轴可能允许治疗性诱导自噬，以抵抗病毒感染和与自噬失调相关的疾病。

Macroautophagy/autophagy is a tightly regulated cellular process integral to homeostasis and innate immunity. As such, dysregulation of autophagy is associated with cancer, neurodegenerative disorders, and infectious diseases. While numerous factors that promote autophagy have been characterized, the key mechanisms that prevent excessive autophagy are less well understood. Here, we identify CSNK2/CK2 (casein kinase 2) as a negative regulator of autophagy. Pharmacological inhibition of CSNK2 activity or siRNA-mediated depletion of CSNK2 increased basal autophagic flux in cell lines and primary human lung cells. Vice versa, ectopic expression of CSNK2 reduced autophagic flux. Mechanistically, CSNK2 interacted with the FLN (filamin)-NHL domain-containing tripartite motif (TRIM) family members TRIM2, TRIM3 and TRIM71. Our data show that recruitment of CSNK2 to the C-terminal NHL domain of TRIM3 lead to its robust phosphorylation at serine 661 by CSNK2. A phosphorylation-defective mutant of TRIM3 was unable to reduce autophagosome numbers indicating that phosphorylation by CSNK2 is required for TRIM-mediated autophagy inhibition. All three TRIMs facilitated inactivation of the ULK1-BECN1 autophagy initiation complex by facilitating ULK1 serine 757 phosphorylation. Inhibition of CSNK2 promoted autophagy upon influenza A virus (IAV) and measles virus (MeV) infection. In line with this, targeting of CSNK2 or depletion of TRIM2, TRIM3 or TRIM71 enhanced autophagy-dependent restriction of IAV, MeV and human immunodeficiency virus 1 (HIV-1). Thus, our results identify the CSNK2-TRIM2, -TRIM3, -TRIM71 axis as a key regulatory pathway that limits autophagy. Targeting this axis may allow for therapeutic induction of autophagy against viral infections and in diseases associated with dysregulated autophagy.