Casein kinase II suppresses autophagy by activating Filamin-NHL containing TRIM proteins

ABSTRACT: Autophagy is a tightly regulated process integral to cellular homeostasis and innate immunity. As such, dysregulation of autophagy is associated with cancer, neurodegenerative disorders, and infectious diseases. While many factors have been characterized that promote autophagy, key players preventing excessive autophagy are less well understood. Here, we identify Casein kinase II (CK2) as a negative regulator of autophagy. Pharmacological inhibition of CK2 activity or siRNA-mediated depletion of CK2 increased basal autophagic flux in cell lines and primary human lung cells. Vice versa, ectopic expression of CK2 reduced autophagic flux. Mechanistically, CK2 interacts with tripartite motif (TRIM) family members TRIM2, TRIM3 and TRIM71 at their shared C-terminal NHL domain. This interaction was required for autophagy inhibition by CK2. TRIM3 was highly phosphorylated by CK2 at serine 661, and a phosphorylation-defective mutant of TRIM3 was unable to reduce autophagy induction. Targeting of the CK2-TRIM axis promoted autophagy during influenza A virus (IAV) and measles virus (MeV) infection. In line with this, inhibition of CK2 enhanced autophagy-dependent restriction of IAV, MeV and human immunodeficiency virus 1 (HIV-1). Thus, our results identify the CK2-TRIM2/3/71 axis as a key regulatory pathway that limits autophagy. Targeting this axis may allow therapeutic induction of autophagy against viral infections and diseases associated with dysregulated autophagy.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Hiv-1 Group M (ncbitaxon:388795) Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Konstantin Sparrer  

PROVIDER: MSV000091956 | MassIVE | Tue May 16 02:23:00 BST 2023

REPOSITORIES: MassIVE