The eukaryotic endoplasmic reticulum (ER) maintains protein homeostasis by eliminating unwanted proteins through the evolutionarily conserved ER-associated degradation (ERAD) pathway. During ERAD, maturation-defective and surplus polypeptides are evicted from the ER lumen and/or lipid bilayer through the process of retrotranslocation and ultimately degraded by the proteasome. An integral facet of the ERAD mechanism is the ubiquitin system, composed of the ubiquitin modifier and the factors for assembling, processing and binding ubiquitin chains on conjugated substrates. Beyond simply marking polypeptides for degradation, the ubiquitin system is functionally intertwined with retrotranslocation machinery to transport polypeptides across the ER membrane.

Summary Insults to endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which elevates protein folding and degradation capacity and attenuates protein synthesis. While a role for ubiquitin in regulating the degradation of misfolded ER-resident proteins is well described, ubiquitin-dependent regulation of translational reprogramming during the UPR remains uncharacterized. Using global quantitative ubiquitin proteomics, we identify evolutionarily conserved, site-specific regulatory ubiquitylation of 40S ribosomal proteins. We demonstrate that these events occur on assembled cytoplasmic ribosomes and are stimulated by both UPR activation and translation inhibition. We further show that ER stress-stimulated regulatory 40S ribosomal ubiquitylation occurs on a timescale similar to eIF2α phosphorylation, is dependent upon PERK signaling, and is required for optimal cell survival during chronic UPR activation. In total, these results reveal regulatory 40S ribosomal ubiquitylation as a previously uncharacterized and important facet of eukaryotic translational control.

A case of primary cutaneous cryptococcal infection is presented and cases of primary cutaneous cryptococcosis in normal and immunocompromised hosts are reviewed. Cutaneous cryptococcosis can occur from local inoculation or dissemination from a distant site of infection. Risk factors associated with development of primary cutaneous cryptococcosis are those which affect cell-mediated immunity, such as corticosteroid usage, solid organ transplantation, sarcoidosis and immunosuppression. The cutaneous manifestations of cryptococcosis are protean and may mimic other cutaneous diseases. Patients with a diagnosis of cryptococcosis from a skin biopsy or culture should undergo evaluation to exclude disseminated disease and an evaluation of cell-mediated immunity. Although some patients do well without antifungal therapy, these patients cannot be discerned prospectively and therefore antifungal therapy appears warranted in all patients with localized disease. Choice of therapy depends on the extent of disease and immunocompetence of the host.