Spastin is required for human immunodeficiency virus-1 efficient replication through cooperation with the endosomal sorting complex required for transport(ESCRT)protein

Human immunodeficiency virus-1(HIV-1)encodes simply 15 proteins and thus depends on multiple host cellular factors for virus reproduction.Spastin,a microtubule severing protein,is an identified HIV-1 dependency factor,but the mechanism regulating HIV-1 is unclear.Here,the study showed that knockdown of spastin inhibited the production of the intracellular HIV-1 Gag protein and new virions through enhancing Gag lysosomal degradation.Further investigation showed that increased sodium tolerance 1(IST1),the subunit of endosomal sorting complex required for transport(ESCRT),could interact with the MIT domain of spastin to regulate the intracellular Gag production.In summary,spastin is required for HIV-1 replication,while spastin-IST1 interaction facilitates virus production by regulating HIV-1 Gag intracellular trafficking and degradation.Spastin may serve as new target for HIV-1 prophylactic and therapy.

Taking out the garbage:cathepsin D and calcineurin in neurodegeneration

Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson＇s, Alzheimer＇s and Huntington＇s diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathep- sin D to the Ca2＋/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson＇s disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2＋ homeostasis as well as lysosomal impairment is connected to a plethora of neurode- generative disorders, this novel interplay might very well impact pathologies beyond Parkinson＇s disease.