Microdomain formation by self-association and cargo interactions, with maintenance of adjacent microdomain separation by active cross-regulation. Illustration of self-associating machinery and cargo within two adjacent microdomains. Association of ESCRT-0, ubiquitinated cargo, and tetraspan proteins promotes degradative microdomain creation, whereas SNX-BAR and WASH/F-actin promote recycling microdomain formation. Ubiquitinated cargo can aid in ESCRT-0 cross-linking, and ubiquitinated tetraspan proteins can provide ubiquitin in trans for cargo that is unable to be ubiquitinated (a). Illustration of RME-8/Hsc70 anchored by SNX-BAR proteins uncoating ESCRT-0/Clathrin from the degradative microdomain at the interface of adjacent domains, helping to prevent invasion of the recycling domain by degradative machinery (b).