NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.

ABSTRACT NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identified an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.

The NF-κB essential modulator NEMO is the core regulatory component of the inhibitor of κB kinase complex, which is a critical checkpoint in canonical NF-κB signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1β, NEMO binds to linear or M1-linked ubiquitin chains generated by LUBAC, promoting its oligomerization and subsequent activation of the associated kinases. Here we show that M1-ubiquitin chains induce phase separation of NEMO and the formation of NEMO assemblies in cells after exposure to IL-1β. Phase separation is promoted by both binding of NEMO to linear ubiquitin chains and covalent linkage of M1-ubiquitin to NEMO and is essential but not sufficient for its phase separation. Supporting the functional relevance of NEMO phase separation in signaling, a pathogenic NEMO mutant, which is impaired in both binding and linkage to linear ubiquitin chains, does not undergo phase separation and is defective in mediating IL-1β–induced NF-κB activation.

The understanding about menstruation among women is lacking in India. Although there are several studies carried out in rural areas about menstruation and its handling, the data was trivial from urban regions in North India. The respondents had a respectable economic background i.e. the family of 45.68% fell in 1-5 lac annual income group while those of 32.34% in 5-10 lac annual income group. They belonged to various religious and cultural backgrounds. In our study we found that 52.05% girls knew about menstruation before menarche and 76.69% also knew about the organs and hormones involved in the process. Moreover, 79.98% said that menstruation keeps their hormones in balance. Significantly greater number of females, i.e. 89.84% used sanitary pads and 85.83% bathed daily. Similarly, significantly higher number of females thought that increase in menstrual flow is directly dependent on increase in physical activities. The mothers of respondents were educated with 41.99% being graduates and 17% being post-graduates and above. To summarize, our study indicated that the young adult girls in the area of study, belonging to different social, cultural and economic backgrounds, are reasonably aware of their needs to maintain good reproductive health. Context: Maintenance of reproductive hygiene during menstruation in young women of Delhi-NCR, India from socio- economic perspective Aims: To comprehend the handling of menstruation by young women in various socio-economic sections in Delhi-NCR, India. Settings and Design: Young college going girls were approached to voluntarily become part of the study and were asked to fill the detailed questionnaire. An informed written consent was taken from each respondent. Methods and Material: The study was undertaken as a curiosity to understand the minds of young female population in Delhi- NCR (India) about menstruation. The survey was carried out from August, 2015 to June, 2016. The survey comprised 974 girls, age ranging from 18-24 years studying in various graduation and post-graduation courses in different colleges of Delhi and National Capital region (NCR), India and included girls who were having normal physiological menstruation. The data was collected by purposive sampling i.e. the girls who volunteered to provide correct information were selected. The girls were asked to fill the detailed questionnaire to elicit information about their socio-economic parameters, menstrual patterns and handling, physical and psychological complaints during menstruation etc. Along with collecting the information during the survey, we also explained the aims of the survey and questionnaire to them. Informed written consent was obtained from each of the respondents. Statistical analysis used: Mostly the data on the annual income of family, education of mother, responses of girls regarding knowledge about menstruation, and sources of first information about menstruation was calculated as percentage. The data on different hygienic practices, viz. sanitary protection, daily bath during menstruation and influence of physical activity on the menstrual flow was arranged in five groups and was tested for normality using Kolmogorov–Smirnoff Test using statistical software, SAS Version 9.0.Normality test confirmed its normal distribution and thereafter the data was subjected to one-way analysis of variance (ANOVA) using the statistical software SAS 9.0 and the means were compared using Tukey’s Test. Results: The families of majority of respondents fell in the income group of 1-5 lackhs (45.68%) followed by 5-10 lackhs (32.34%). While 52.05% girls knew about menstruation before menarche, 46.81% did not know about the process. Majority of the girls (76.69%) knew about the hormones and organs playing role during menstruation while 19.81% did not know about them, with 3.49% not having any idea about hormones. Also, 79.98% knew that menstruation is important to maintain the normal levels of hormones in body while 13.76% did not believe in this and 6.26% did not know anything about such correlation. Mothers were the first source of information about menstruation (52.36%) followed by school/teachers (19.61%) and friends (12.11%). Statistically significant number of respondents (89.84%) used sanitary pads during menstruation while some (1.64%) used cloth as sanitary protection. Significantly greater numbers of girls were concerned about hygiene during menstruation as 85.83% bathed daily in this period. Similarly, significantly large number of respondents believed that physical activity increased the menstrual flow (62.32%). Conclusions: The young women of Delhi-NCR are very well aware of their needs to maintain good reproductive hygiene during menstruation. This observation was beyond the limits of the social and economic strata they belonged to. Moreover, the social and economic status of respondents did not seem to interfere in adopting better methods to maintain a better reproductive hygiene.