TANK-binding kinase 1 (TBK1) is a druggable multifunctional kinase that exerts a broad spectrum of functions in cells. These range from innate immunity, inflammation and interferon (IFN) signaling, through selective autophagy, specifically mitophagy and xenophagy, to energy homeostasis. Thus, it is not surprising that TBK1 is involved in many cellular signaling pathways that contribute to diverse pathologies. In this review the role of TBK1 in autophagic signaling, especially mitophagy and xenophagy, and its contribution to oncogenesis or neurodegenerative diseases will be discussed.

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.

The major histocompatibility complex (MHC) class I molecules present peptide antigens to MHC class I‐restricted CD8+ T lymphocytes to elicit an effective immune response. The conventional antigen‐processing pathway for MHC‐I presentation depends on proteasome‐mediated peptide generation and peptide loading in the endoplasmic reticulum by members of the peptide loading complex. Recent discoveries in this field highlight the role of alternative MHC‐I peptide loading and presentation pathways, one of them being autophagy. Autophagy is a cell‐intrinsic degradative pathway that ensures cellular homoeostasis and plays critical roles in cellular immunity. In this review article, we discuss the role of autophagy in MHC class I‐restricted antigen presentation, elucidating new findings on the crosstalk of autophagy and ER‐mediated MHC‐I peptide presentation, dendritic cell‐mediated cross‐presentation and also mechanisms governing immune evasion. A detailed molecular understanding of the key drivers of autophagy‐mediated MHC‐I modulation holds promising targets to devise effective measures to improve T cell immunotherapies.

Autophagy is a central mechanism of cellular homeostasis through the degradation of a wide range of cellular constituents. However, recent evidence suggests that autophagy actively provides information to neighboring cells via a process called secretory autophagy. Secretory autophagy couples the autophagy machinery to the secretion of cellular content via extracellular vesicles (EVs). EVs carry a variety of cargo, that reflect the pathophysiological state of the originating cells and have the potential to change the functional profile of recipient cells, to modulate cell biology. The immune system has evolved to maintain local and systemic homeostasis. It is able to sense a wide array of molecules signaling disturbed homeostasis, including EVs and their content. In this review, we explore the emerging concept of secretory autophagy as a means to communicate cellular, and in total tissue pathophysiological states to the immune system to initiate the restoration of tissue homeostasis. Understanding how autophagy mediates the secretion of immunogenic factors may hold great potential for therapeutic intervention.

Significance: Through conducting quantitative proteomics upon Salmonella infection, we identified a SIK2 signaling network, implementing the kinase into a so far concealed biological function. Our data exposed SIK2 as a central orchestrator of an actin regulatory network, coordinating the stability of Salmonella -containing vacuole (SCV) and cellular actin assembly, in order to limit the acute phase of the infection. Most strikingly, SIK2 is not exclusively acting locally on actin assembly associated with the SCV but impacts the actin cytoskeleton architecture in its entirety upon Salmonella infection. Our work provides a mechanistic framework for how the actin cytoskeleton is regulated and how it helps to control an acute Salmonella infection.

(1) Background: Intrinsic defense mechanisms are pivotal host strategies to restrict viruses already at early stages of their infection. Here, we addressed the question of how the autophagy receptor sequestome 1 (SQSTM1/p62, hereafter referred to as p62) interferes with human cytomegalovirus (HCMV) infection. (2) Methods: CRISPR/Cas9-mediated genome editing, mass spectrometry and the expression of p62 phosphovariants from recombinant HCMVs were used to address the role of p62 during infection. (3) Results: The knockout of p62 resulted in an increased release of HCMV progeny. Mass spectrometry revealed an interaction of p62 with cellular proteins required for nucleocytoplasmic transport. Phosphoproteomics further revealed that p62 is hyperphosphorylated at position S272 in HCMV-infected cells. Phosphorylated p62 showed enhanced nuclear retention, which is concordant with enhanced interaction with viral proteins relevant for genome replication and nuclear capsid egress. This modification led to reduced HCMV progeny release compared to a non-phosphorylated version of p62. (4) Conclusions: p62 is a restriction factor for HCMV replication. The activity of the receptor appears to be regulated by phosphorylation at position S272, leading to enhanced nuclear localization, viral protein degradation and impaired progeny production.