Compared to the tidy and immunologically silent death during apoptosis, necrosis seems like a chaotic and unorganized demise. However, we now recognize that there is a method to its madness, as many forms of necrotic cell death are indeed programmed and function beyond lytic cell death to support homeostasis and immunity. Inherently more immunogenic than their apoptotic counterpart, programmed necrosis, such as necroptosis, pyroptosis, ferroptosis, and NETosis, releases inflammatory cytokines and danger-associated molecular patterns (DAMPs), skewing the milieu to a pro-inflammatory state. Moreover, impaired clearance of dead cells often leads to inflammation. Importantly, these pathways have all been implicated in inflammatory and autoimmune diseases, therefore careful understanding of their molecular mechanisms can have long lasting effects on how we interpret their role in disease and how we translate these mechanisms into therapy.

Rubicon (Rubcn) was initially identified as a component of the Class III PI3K complex and a negative regulator of canonical autophagy and endosomal trafficking. However, Rubicon has attracted the most notoriety because of its critical role in LC3‐associated phagocytosis (LAP), a form of noncanonical autophagy that utilizes some components of the autophagy machinery to process extracellular cargo. Additionally, Rubicon has been identified as a key modulator of the inflammatory response and viral replication. In this review, we discuss the known functions of Rubicon in LAP and other signaling pathways and examine the disease pathologies associated with Rubicon dysfunction in animal models and humans.

Bone Research, Published online: 7 July 2015; | doi:10.1038/boneres.2015.20

Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family (n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations (n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis.