LUBAC assembles a signaling platform at mitochondria for signal amplification and shuttling of NF-ĸB to the nucleus

Abstract

Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling, however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here we show that the NF-ĸB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF-ĸB to the nucleus. TNF induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-ĸB is locally activated and transported to the nucleus by mitochondria, resulting in an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner. Notably, TNF-induced stabilization of the mitochondrial kinase PINK1 contributes to signal amplification by antagonizing the M1-ubiquitin-specific deubiquitinase OTULIN.

LUBAC and NF‐κB trigger a nuclear response from mitochondria

“…This function may be connected to NF‐κB, given Mfn2 promotes cytokine production and the activation of NF‐κB in macrophages (Tur et al , 2020). Consistent with a role of mitochondria–nucleus contacts for their findings, Wu et al (2022) indeed observe increased HOIP‐dependent tethering signals as measured with a fluorescent mitochondria–nucleus SPLICS probe upon TNFR signaling. This suggests that LUBAC‐controlled TNFR signaling activates mitochondria–nucleus tethers, perhaps TSPO, or mitofusin‐2.…”

“…Taken together, the findings by Wu et al (2022) establish LUBAC as a key control step for the switch from mitochondrial apoptotic to mitochondrial prosurvival signaling. This is associated with mitochondria–nucleus tethering and facilitated import of NF‐κB into the nucleus.…”

“…Wu et al (2022) have now significantly expanded the spatial relationships and consequences of LUBAC and OTULIN‐controlled M1 ubiquitination. They show that from their location to the outer mitochondrial membrane, both regulators of NF‐κB signaling components protect mitochondria from apoptosis, but also control NF‐κB signal progression in the early phases of TNF signaling, before the induction of the NF‐κB transcriptional response.…”

“…An important question is why cells employ mitochondria as a platform for NF‐κB signaling. Wu et al (2022) proposed a hypothesis that mitochondria might equip NF‐κB signaling with a mobile platform that interacts with other organelles, including the nucleus. For these interactions, mitochondria typically use interorganellar tethers, as well as mitochondrial motor proteins to form temporary or stable membrane contact sites (MCS) with the endoplasmic reticulum (ER), lysosomes or the nucleus.…”