Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD.

Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.

JAK-STAT signaling maintains homeostasis in T cells and macrophages.

Immune cells need to sustain a state of constant alertness over a lifetime. Yet, little is known about the regulatory processes that control the fluent and fragile balance that is called homeostasis. Here we demonstrate that JAK-STAT signaling, beyond its role in immune responses, is a major regulator of immune cell homeostasis. We investigated JAK-STAT-mediated transcription and chromatin accessibility across 12 mouse models, including knockouts of all STAT transcription factors and of the TYK2 kinase. Baseline JAK-STAT signaling was detected in CD8+ T cells and macrophages of unperturbed mice-but abrogated in the knockouts and in unstimulated immune cells deprived of their normal tissue context. We observed diverse gene-regulatory programs, including effects of STAT2 and IRF9 that were independent of STAT1. In summary, our large-scale dataset and integrative analysis of JAK-STAT mutant and wild-type mice uncovered a crucial role of JAK-STAT signaling in unstimulated immune cells, where it contributes to a poised epigenetic and transcriptional state and helps prepare these cells for rapid response to immune stimuli.

Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.

Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an "autophagosome" on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.

TYK2 in Tumor Immunosurveillance.

We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue 'Targeting STAT3 and STAT5 in Cancer' of Cancers.