Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia1-3. We report that Autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and required for a timely onset of Gli2-induced skin tumorigenesis in mice. Induction of Aire mRNA in keratinocytes depends upon a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K4. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each are bound to a specific promoter region featuring a NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent pro-inflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.

SummaryDespite recent advances in understanding the functions of autophagy in developmental and pathological conditions, the underlying mechanism of where and how autophagosomal structures acquire membrane remains enigmatic. Here, we provide evidence that postGolgi membrane traffic plays a crucial role in autophagosome formation. Increased secretion of constitutive cargo from the trans-Golgi network (TGN) to the plasma membrane induced the formation of microtubule-associated protein light chain 3 (LC3)-positive structures. At the early phase of autophagy, LC3 associated with and then budded off from a distinct TGN domain without constitutive TGN-to-plasma cargo and TGN-to-endosome proteins. The clathrin adaptor protein AP1 and clathrin localized to starvation-and rapamycin-induced autophagosomes. Dysfunction of the AP1-dependent clathrin coating at the TGN but not at the plasma membrane prevented autophagosome formation. Our results thus suggest an essential role of the TGN in autophagosome biogenesis, providing membrane to autophagosomes through an AP1-dependent pathway.

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A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD.