Analysis of the turnover of unassembled proteins during the assembly of the erythroid membrane skeleton has revealed that alpha- and beta-spectrin, two structurally related, high molecular weight proteins, are degraded in a selective manner by two distinct intracellular pathways. Unassembled alpha-spectrin (t1/2 approximately equal to 2 hr) is degraded by a system with all the pharmacological characteristics of a membrane-bound, lysosomal-type pathway. This result illustrates for the first time the selective degradation of an intracellular short-lived, unassembled protein by a lysosomal pathway. In contrast, unassembled beta-spectrin is degraded extremely rapidly (t1/2 approximately equal to 15-20 min at 38 degrees C) by a soluble cytoplasmic system in an apparently ATP-independent manner. These observations suggest that the selective and rapid degradation of beta-spectrin serves an important regulatory role in the topogenesis of the spectrin-based membrane skeleton in the chicken erythrocyte.