Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of ‘self-eating’ where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis

Multi-localized proteins: the peroxisome-mitochondria connection

This is the author accepted manuscript. The final version is available from Springer via the link in this recordPeroxisomes and mitochondria are dynamic, multifunctional organelles that play pivotal cooperative roles in the metabolism of cellular lipids and reactive oxygen species. Their functional interplay, the “peroxisome-mitochondria connection”, also includes cooperation in anti-viral signalling and defence, as well as coordinated biogenesis by sharing key division proteins. In this review, we focus on multi-localised proteins which are shared by peroxisomes and mitochondria in mammals. We first outline the targeting and sharing of matrix proteins which are involved in metabolic cooperation. Next, we discuss shared components of peroxisomal and mitochondrial dynamics and division, and we present novel insights into the dual targeting of tail-anchored membrane proteins. Finally, we provide an overview of what is currently known about the role of shared membrane proteins in disease. What emerges is that sharing of proteins between these two organelles plays a key role in their cooperative functions which, based on new findings, may be more extensive than originally envisaged. Gaining a better insight into organelle interplay and the targeting of shared proteins is pivotal to understanding how organelle cooperation contributes to human health and disease.This work was supported by the Biotechnology and Biological Sciences Research Council (BB/K006231/1, BB/N01541X/1 to M.S.). M.I. is supported by the German Research Foundation (DFG 397476530) and MEAMEDMA Anschubförderung, Medical Faculty Mannheim, University of Heidelberg. J.P. is supported by CLES, University of Exeter